Source document: https://docs-lawep.s3.us-east-2.amazonaws.com/1697632442840.pdf (Australia)
J. Nat.

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2007, 70, 461-477 461 Natural Products as Sources of New Drugs over the Last 25 Years^ David J. Newman* and Gordon M. Cragg Natural Products Branch, DeVelopmental Therapeutics Program, DiVision of Cancer Treatment and Diagnosis, National Cancer Institute-Frederick, P.O.

Box B, Frederick, Maryland 21702 ReceiVed October 10, 2006 This review is an updated and expanded version of two prior reviews that were published in this journal in 1997 and 2003.
In the case of all approved agents the time frame has been extended to include the 251/2 years from 01/1981 to 06/2006 for all diseases worldwide and from 1950 (earliest so far identified) to 06/2006 for all approved antitumor drugs worldwide.

We have continued to utilize our secondary subdivision of a “natural product mimic” or “NM” to join the original primary divisions.
From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well.

Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 155 small molecules, 73% are other than “S” (synthetic), with 47% actually being either natural products or directly derived therefrom.
In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the antiinfective area being dependent on natural products and their structures.

Although combinatorial chemistry techniques have succeeded as methods of optimizing structures and have, in fact, been used in the optimization of many recently approved agents, we are able to identify only one de noVo combinatorial compound approved as a drug in this 25 plus year time frame.
We wish to draw the attention of readers to the rapidly evolving recognition that a significant number of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the “host from whence it was isolated”, and therefore we consider that this area of natural product research should be expanded significantly.
It is over nine years since the publication of our first,1 and three years since the second,2 analysis of the sources of new and approved drugs for the treatment of human diseases, both of which indicated that natural products continued to play a highly significant role in the drug discovery and development process.
That this influence of Nature in one guise or another has continued is shown by inspection of the information given below, where with the advantage of now over 25 years of data, we have been able to refine the system, eliminating a few duplicative entries that crept into the original data sets.
In particular, as behooves authors from the National Cancer Institute (NCI), in the specific case of cancer treatments, we have gone back to consult the records of the FDA and added to these, comments from investigators who have informed us over the past two years of compounds that may have been approved in other countries and that were not captured in our earlier searches.

These cancer data will be presented as a stand-alone section as well as including the last 25 years of data in the overall discussion.
As we mentioned in our 2003 review,2 the development of high- throughput screens based on molecular targets had led to a demand for the generation of large libraries of compounds to satisfy the enormous capacities of these screens.

As we mentioned at that time, the shift away from large combinatorial libraries has continued, with the emphasis now being on small, focused (100 to 3000) collections that contain much of the “structural aspects” of natural products.
Various names have been given to this process, including “Diversity Oriented Syntheses”,3-6 but we prefer to simply say “more natural product-like”, in terms of their combinations of heteroatoms and significant numbers of chiral centers within a single molecule,7 or even “natural product mimics” if they happen to be direct competitive inhibitors of the natural substrate.
It should also be pointed out that Lipinski’s fifth rule effectively states that the first four rules do not apply to natural products or to any molecule ^ Dedicated to the late Dr. Kenneth L. Rinehart of the University of Illinois at Urbana-Champaign for his pioneering work on bioactive natural products.

* To whom correspondence should be addressed.

Tel: (301) 846-5387.

Fax: (301) 846-6178.

E-mail: newmand@mail.nih.gov.


that is recognized by an active transport system when considering “druggable chemical entities”.8-10 Although combinatorial chemistry in one or more of its manifestations has now been used as a discovery source for approximately 70% of the time covered by this review, to date, we can find only one de noVo new chemical entity (NCE) reported in the public domain as resulting from this method of chemical discovery and approved for drug use anywhere.
This is the antitumor compound known as sorafenib (Nexavar, 1) from Bayer, approved by the FDA in 2005.

It was known during development as BAY- 43-9006 and is a multikinase inhibitor, targeting several serine/ threonine and receptor tyrosine kinases (RAF kinase, VEGFR-2, VEGFR-3, PDGFR-beta, KIT, and FLT-3) and is in multiple clinical trials as both combination and single-agent therapies at the present time, a common practice once approved for one class of cancer treatment.
As mentioned by the authors in prior reviews on this topic and others, the developmental capability of combinatorial chemistry as a means for structural optimization once an active skeleton has been identified is without par.
The expected surge in productivity, however, has not materialized; thus, the number of new active substances (NASs), also known as New Chemical Entities (NCEs), which we consider to encompass all molecules, including biologics and vaccines, from our data set hit a 24-year low of 25 in 2004 (though 28% of these were assigned to the ND category), with a rebound to 54 in 2005, with 24% being N or ND and 37% being biologics (B) or vaccines (V).
Fortunately, however, research being conducted by groups such as Danishefsky’s, Ganesan’s, Nicolaou’s, Porco’s, Quinn’s, Schreiber’s, Shair’s, Waldmann’s, and Wipf’s is continuing the modification of active natural product skeletons as leads to novel agents, so in due course, the numbers of materials developed by linking Mother Nature to combinatorial synthetic techniques should increase.
This aspect, plus the potential contribu- tions from the utilization of genetic analyses of microbes, will be discussed at the end of this review.

Against this backdrop, we now present an updated analysis of the role of natural products in the drug discovery and development process, dating from 01/1981 through 06/2006.

As in our earlier 10.1021/np068054v This article not subject to U.S.

Copyright.

Published 2007 by the Am.

Chem.

Soc.

and the Am.

Soc.

of Pharmacogn.


Published on Web 02/20/2007 462 Journal of Natural Products, 2007, Vol.

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70, No.

3 ReViews analyses,1,2 we have consulted the Annual Reports of Medicinal Chemistry, in this case from 1984 to 2005,11-32 and have produced a more comprehensive coverage of the 1981-2006 time frame through addition of data from the publication Drug News and PerspectiVe33-49 and searches of the Prous Integrity database, as well as by including information from individual investigators.
We also updated the biologicals section of the data set using information culled from disparate sources that culminated in a recent review (2005) on biopharmaceutical drugs.50 We have also included relevant references in a condensed form in Tables 1-5, 8, and 9; otherwise the numbers of references cited in the review would become overwhelming.

In these cases, “ARMC ##” refers to the volume of Annual Reports in Medicinal Chemistry together with the page on which the structure(s) can be found.
Similarly, “DNP ##” refers to the volume of Drug News and PerspectiVe and the corresponding page(s), and an “I ######” is the accession number in the Prous Integrity database.

Finally, we have used “Boyd” to refer to a review article51 on clinical antitumor agents and “M’dale” to refer to Martindale52 with the relevant page noted.

It should be noted that the “Year” header in all tables is the “Year of Introduction” of the drug.
In some cases there are discrepancies between sources as to the actual year due to differences in definitions.

We have generally taken the earliest year in the absence of further information.

Results As before, we have covered only New Chemical Entities (NCEs) in the present analysis.

If one reads the FDA and PhRMA Web sites, the numbers of NDA approvals are in the high tens to low hundred numbers for the last few years.
If, however, one removes combinations of older drugs and old drugs with new indications, and/or improved delivery systems, then the number of true NCEs is only in the 20s to just over 50 per year for the last five or so years (see Figures 2 and 5).

As in our earlier analyses,1,2 the data have been analyzed in terms of numbers and classified according to their origin using both the previous major categories and their subdivisions.

Major Categories of Sources.


The major categories used are as follows: “B” Biological; usually a large (>45 residues) peptide or protein either isolated from an organism/cell line or produced by biotech- nological means in a surrogate host.

“N” Natural product.

“ND” Derived from a natural product and is usually a semisyn- thetic modification.

“S” Totally synthetic drug, often found by random screening/ modification of an existing agent.
“S*” Made by total synthesis, but the pharmacophore is/was from a natural product.

“V” Vaccine.

Subcategory.

“NM” Natural product mimic (see rationale and examples below).

(For amplification as to the rationales used for categorizing using the earlier the reader should consult the above subdivisions, reviews.1,2) In the field of anticancer therapy, the advent in 2001 of Gleevec, a protein tyrosine kinase inhibitor, was justly heralded as a breakthrough in the treatment of leukemia.
This compound was classified as an “NM” on the basis of its competitive displacement of the natural substrate ATP, whose intracellular concentrations can approach 5 mM.
We have continued to classify PTK and other kinase inhibitors that are approved as drugs under the “/NM” category for exactly the same reasons as elaborated in the 2003 review2 and have continued to extend it to cover other direct inhibitors/antagonists of the natural substrate/receptor interac- tion whether obtained by direct experiment or by in silico studies followed by direct assay in the relevant system.
Similarly, a number of new peptidic drug entities, though formally synthetic in nature, are simply produced by synthetic methods rather than by the use of fermentation or extraction.

In some cases, an end group might have been changed for ease of recovery.

In addition, a number of compounds produced totally by synthesis are, in fact, isosteres of the peptidic substrate and are thus “natural product mimics” in the truest sense of the term.
For further information on this area, interested readers should consult the excellent review by Hruby.53 As an example of what can be found by studies around relatively simple peptidomimics of the angiotensin II structure, the recent paper of Wan et al.54 demonstrating the modification of the known but nonselective AT1/AT2 agonist L-162313 (2, itself related to the sartans) into the highly selective AT2 agonist (3) (a peptidomimetic structure) led to the very recent identification of short pseudo- peptides exemplified by 4, which is equipotent (binding affinity ) 500 pM) with angiotensin II and has a better than 20 000-fold selectivity versus AT1, whereas angiotensin II has only a 5-fold binding selectivity in the same assay.55 It will be interesting to see if any compounds such as these will end up as cardiovascular agents since it has been demonstrated that activation of the AT2 receptor affects cardiac remodeling and leads to reduced blood pressure.56 In the area of modifications of natural products by combinatorial methods to produce entirely different compounds that may bear little if any resemblance to the original, but are legitimately assignable to the “NM” category, citations are given in previous reviews.3,57-64 In addition, one should consult the recent reports from Waldmann’s group65,66 and those by Ganesan,67 Shang and Tan,68 Constantino,69 and Violette et al.70 on the use of privileged structures as skeletons around which to build libraries.
Another paper of interest in this regard is the editorial by Macarron from GSK,9 as this may be the first time where data from industry on the results of HTS screens of combichem libraries versus potential targets were reported with a discussion of lead discovery rates.

In this paper, Macarron reemphasizes the fifth Lipinski rule, which is often ignored; “natural products do not obey the other four”.

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3 463 Table 1.
New Chemical Entities and Medical Indications by Source of Compound 01/1981-06/2006a,b indication total B analgesic anesthetic anti-Alzheimer’s anti-Parkinsonism antiallergic antianginal antiarrhythmic antiarthritic antiasthmatic antibacterial anticancer anticoagulant antidepressant antidiabetic antiemetic antiepileptic antifungal antiglaucoma antihistamine antihyperprolactinemia antihypertensive antiinflammatory antimigraine antiobesity antiparasitic antipsoriatic antipsychotic antithrombotic antiulcer antiviral anxiolytic benign prostatic hypertrophy bronchodilator calcium metabolism cardiotonic chelator & antidote contraception diuretic gastroprokinetic hematopoiesis hemophilia hormone hormone replacement therapy hypnotic hypocholesterolemic hypolipidemic immunomodulator immunostimulant immunosuppressant male sexual dysfunction multiple sclerosis muscle relaxant neuroleptic nootropic osteoporosis platelet aggregation inhibitor respiratory distress syndrome urinary incontinence vasodilator vulnerary N 1 1 1 1 10 9 1 2 1 1 1 3 1 1 3 5 1 ND S origin of drug S/NM 2 3 5 6 6 12 13 4 1 3 5 14 1 3 2 5 1 2 1 1 3 1 1 2 1 6 1 1 2 S* 2 11 1 1 2 1
 2 2 1 20 1 3 S*/NM V grand total a Where there were e 3 NCEs per indication in the time frame 01/1981-06/2006, the number of NCEs totaled 174.
These were assignable as B, 41; N, 12; ND, 38; S, 54; S/NM, 10; S*, 5; S*/NM, 7; V, 7. b The indications for these 174 drugs are as follows: 5 alpha-reductase inhibitor, ADHD, CNS stimulant, COPD, Crohn’s disease, Fabry’s disease, Gaucher’s disease, IBS, Lyme disease, MI, acute, MMRC, PCP/toxoplasmosis, Pompe’s disease, abortifacient, acromelagy, actinic keratoses, adjuvant/colorectal cancer, alcohol deterrent, anabolic metabolism, analeptic, anemia, angina, anti-sickle cell anemia, antiacne, antiathersclerotic, anticholelithogenic, anticonvulsant, antidiarrheal, antidote, antiemphysemic, antiestrogenic, antihyperuricemia, antihypotensive, antinarcolepsy, antinarcotic, antinauseant, antiperistaltic, antiprogestogenic, antirheumatic, antisecretory, antisepsis, antiseptic, antispasmodic, antispastic, antitussive, antityrosinaemia, antixerostomia, benzodiazepine antagonist, beta-lactamase inhibitor, blepharospasm, bone disorders, bone morphogenesis, bowel evacuant, cardioprotective, cardiovascular disease, cervical dystonia, chelator, choleretic, chronic idiopathic constipation, cognition enhancer, congestive heart failure, cystic fibrosis, cytoprotective, diabetic foot ulcers, digoxin toxicity, diphtheria-pertussis- tetanus, dysuria, enzyme, erythropoiesis, expectorant, gastroprotectant, genital warts, hematological, hemostatic, hepatoprotectant, hyperammonemia, homocystinuria, hyperparathyroidism, hyperphenylalaninemia, hyperphosphatemia, hypoammonuric, hypocalciuric, hypogonadism, iron chelator, joint
 lubricant, lipoprotein disorders, macular degeneration, mucolytic, mucopolysaccharidosis, mucositis, myleodysplasia, narcolepsy, nasal decongestant, neuropathic pain, neuroprotective, opiate detoxification, osteoarthritis, ovulation, pancreatic disorders, pancreatitis, pertussis, photosensitizer, pituitary disorders, porphyria, premature birth, progestogen, psychostimulant, purpura fulminans, rattlesnake antivenom, reproduction, restenosis, sclerosant, secondary hyperthryoidism, sedative, skin photodamage, smoking cessation, strabismus, subarachnoid hemorrhage, thrombocytopenia, treatment of GH deficiency, ulcerative colitis, urea cycle disorders, urolithiasis.
39 464 Journal of Natural Products, 2007, Vol.

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3 ReViews Table 2.
Antibacterial Drugs from 01/1981 to 06/2006 Organized Alphabetically by Generic Name within Source generic name RV-11 carumonam daptomycin fosfomycin trometamol isepamicin micronomicin sulfate miokamycin mupirocin netilimicin sulfate teicoplanin apalcillin sodium arbekacin aspoxicillin astromycin sulfate azithromycin aztreonam biapenem cefbuperazone sodium cefcapene pivoxil cefdinir cefditoren pivoxil cefepime cefetamet pivoxil HCl cefixime cefmenoxime HCl cefminox sodium cefodizime sodium cefonicid sodium cefoperazone sodium ceforanide cefoselis cefotetan disodium cefotiam HCl cefozopran HCl cefpimizole cefpiramide sodium cefpirome sulfate cefpodoxime proxetil cefprozil cefsoludin sodium ceftazidime cefteram pivoxil ceftibuten ceftizoxime sodium ceftriaxone sodium cefuroxime axetil cefuzonam sodium clarithromycin dalfopristin dirithromycin doripenem ertapenem sodium erythromycin acistrate flomoxef sodium flurithromycin ethylsuccinate fropenam imipenem/cilastatin lenampicillin HCI loracarbef meropenem moxalactam disodium panipenem/betamipron quinupristin rifabutin rifamixin rifapentine rifaximin rokitamycin roxithromycin sultamycillin tosylate tazobactam sodium telithromycin temocillin disodium tigecycline trade name Zalig Amasulin Cubicin Monuril Isepacin Sagamicin Miocamycin Bactroban Netromicine Targocid Lumota Habekacin Doyle Fortimicin Sunamed Azactam Omegacin Tomiporan Flomox Cefzon Meiact Maxipime Globocef Cefspan Tacef Meicelin Neucef Monocid Cefobis Precef Wincef Yamatetan Pansporin Firstcin Ajicef
 Sepatren Cefrom Banan Cefzil Takesulin Fortam Tomiron Seftem Epocelin Rocephin Zinnat Cosmosin Klaricid Synercid Nortron Finibax Invanz Erasis Flumarin Ritro Farom Zienam Varacillin Lorabid Merrem Shiomarin Carbenin Synercid Mycobutin Normix Rifampin Rifacol Ricamycin Rulid Unasyn Tazocillin Ketek Temopen Tygacil year introduced 1992
reference ARMC 25 ARMC 24 ARMC 39 I 112334 ARMC 24 I 091082 ARMC 21 ARMC 21 I 070366 ARMC 24 I 091130 ARMC 26 ARMC 23 ARMC 21 ARMC 24 ARMC 20 ARMC 38 ARMC 21 ARMC 33 ARMC 27 ARMC 30 ARMC 29 ARMC 28 ARMC 23 ARMC 19 ARMC 23 ARMC 26 ARMC 20 I 127130 ARMC 20 ARMC 34 ARMC 20 I 091106 ARMC 31 ARMC 23 ARMC 21 ARMC 28 ARMC 25 ARMC 28 I 091108 ARMC 19 ARMC 23 ARMC 28 I 070260 I 091136 ARMC 23 ARMC 23 ARMC 26 ARMC 35 ARMC 29 DNP 19 ARMC 38 ARMC 24 ARMC 24 ARMC 33 ARMC 33 ARMC 21 ARMC 23 ARMC 28 ARMC 30 I 070301 ARMC 30 ARMC 35 ARMC 28 ARMC 23 ARMC 24 ARMC 21 ARMC 22 ARMC 23 ARMC 23 ARMC 28 DNP 15 ARMC 20 DNP 19 page source N N N N N N N N N N ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND Journal of Natural Products, 2007, Vol.
70, No.

3 465 page source ReViews Table 2.
Continued generic name trade name year introduced balafloxacin ciprofloxacin enoxacin fleroxacin gatilfloxacin gemifloxacin mesilate grepafloxacin levofloxacin linezolid lomefloxacin moxifloxacin HCl nadifloxacin norfloxacin ofloxacin pazufloxacin pefloxacin mesylate prulifloxacin rufloxacin hydrochloride sparfloxacin taurolidine temafloxacin hydrochloride tosufloxacin trovafloxacin mesylate brodimoprin ACWY meningoccal PS vaccine MCV-4 h influenzae b vaccine h influenzae b vaccine meningitis b vaccine meningococcal vaccine meningococcal vaccine meningococcal vaccine oral cholera vaccine pneumococcal vaccine vi polysaccharide typhoid vaccine Q-Roxin Ciprobay Flumark Quinodis Tequin Factive Vaxor Floxacin Zyvox Uniquin Avelox Acuatim Noroxin Tarivid Pasil Perflacine Sword Qari Spara Taurolin Temac Ozex Trovan Hyprim Mencevax Menactra Hibtitek Prohibit MeNZB NeisVac-C Menjugate Menigetec Orochol Prevnar Typherix reference ARMC 38 ARMC 22 ARMC 22 ARMC 28 ARMC 35 ARMC 40 DNP 11 ARMC 29 DNP 14 ARMC 25 ARMC 35 ARMC 29 ARMC 19 ARMC 21 ARMC 38 ARMC 21 ARMC 38 ARMC 28 ARMC 29 I 107771 ARMC 27 ARMC 26 ARMC 34 ARMC 29 I 420128 DNP 19 DNP 03 DNP 03 DNP 18 DNP 14 DNP 14 DNP 14 DNP 08 DNP 14 DNP Table 3.
Antifungal Drugs from 01/1981 to 06/2006 Organized Alphabetically by Generic Name within Source generic name interferon gamma-n1 anidulafungin caspofungin acetate micafungin sodium amorolfine hydrochloride butoconazole ciclopirox olamine cloconazole HCI eberconazole fenticonazole nitrate fluconazole flutrimazole fosfluconazole itraconazole ketoconazole lanoconazole luliconazole naftifine HCI neticonazole HCI oxiconazole nitrate posaconazole sertaconazole nitrate sulconazole nitrate terconazole tioconazole voriconazole butenafine hydrochloride liranaftate terbinafine hydrochloride trade name OGamma100 Eraxis Cancidas Fungard Loceryl Femstat Loprox Pilzcin Ebernet Lomexin Diflucan Micetal Prodif Sporanox Nizoral Astat Lulicon Exoderil Atolant Oceral Noxafil Dermofix Exelderm Gyno-Terazol Trosyl Vfend Mentax Zefnart Lamisil year introduced 1996 2006 2001 2002 1991 1986 1982 1986 2005 1987 1988 1995 2003 1988 1981 1994 2005 1984 1993 1983 2005 1992 1985 1983 1983 2002 1992 2000 1991 reference DNP 10 I 194685 DNP 15 ARMC 38 ARMC 27 ARMC 22 I 070449 ARMC 22 DNP 19 ARMC 23 ARMC 24 ARMC 31 DNP 17 ARMC 24 I 116505 ARMC 30 DNP 19 ARMC 20 ARMC 29 ARMC 19 DNP 19 ARMC 28 ARMC 21 ARMC 19 ARMC 19 ARMC 38 ARMC 28 DNP 14 ARMC 27 page 13 36 360 322 318 318 42 334 303 343 49 305 302 42 321 341 322 42 336 332 324 324 370 327 21 334 S S S S S S S S S S S S S S S S S S S S S S S S*/NM V V V V V V V V V V V source B ND ND ND S S S S S S S S S S S S S S S S S S S S S S S/NM S/NM S/NM Overview of Results.
The data that we have analyzed in a variety of ways are presented as a series of bar graphs and pie charts and two major tables in order to establish the overall pictures and then are further subdivided into some major therapeutic areas using a tabular format.

Except where noted, the time frame covered was 01/1981-06/2006: ¥ New Approved Drugs: With all source categories (Figure 1) ¥ New Approved Drugs: By source/year (Figure 2) 466 Journal of Natural Products, 2007, Vol.

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3 ReViews Table 4.
Antiviral Drugs from 01/1981 to 06/2006 Organized Alphabetically by Generic Name within Source generic name trade name year introduced immunoglobulin intravenous interferon alfa interferon alfa-2b interferon alfa-n3 interferon alfacon-1 interferon beta palivizumab peginterferon alfa-2a peginterferon alfa-2b resp syncytial virus IG thymalfasin interferon alfa-n1 enfuvirtide zanamivir delavirdine mesylate efavirenz foscarnet sodium imiquimod nevirapine propagermanium rimantadine HCI oseltamivir abacavir sulfate acyclovir adefovir dipivoxil cidofovir didanosine emtricitabine entecavir epervudine famciclovir ganciclovir inosine pranobex lamivudine penciclovir sorivudine stavudine tenofovir disoproxil fumarate valaciclovir HCl valganciclovir zalcitabine zidovudine amprenavir atazanavir darunavir fomivirsen sodium fosamprenevir indinavir sulfate lopinavir neflinavir mesylate ritonavir saquinavir mesylate tipranavir (no generic name) MR vaccine anti-Hep B immunoglobulin attenuated chicken pox vaccine hepatitis A and B vaccine hepatitis B vaccine hepatitis a vaccine hepatitis a vaccine hepatitis a vaccine hepatitis b vaccine hepatitis b vaccine hepatitis b vaccine hepatitis b vaccine hepatitis b vaccine inact hepatitis a vaccine influenza vaccine influenza virus (live) rotavirus vaccine rotavirus vaccine rotavirus vaccine rubella vaccine varicella virus vaccine zoster vaccine live (no generic name) Gammagard Liquid Alfaferone Viraferon Alferon N Infergen Frone Synagis Pegasys Pegintron RespiGam Zadaxin Wellferon Fuzeon
 Relenza Rescriptor Sustiva Foscavir Aldara Viramune Serosion Roflual Tamiflu Ziagen Zovirax Hepsera Vistide Videx Emtriva Baraclude Hevizos Famvir Cymevene Imunovir Epivir Vectavir Usevir Zerit Viread Valtrex Valcyte Hivid Retrovir Agenerase Reyataz Prezista Vitravene Lexiva Crixivan Kaletra Viracept Norvir Invirase Aptivus VariZIG Mearubik HepaGam B Merieux Varicella Vaccine Ambirix Fendrix Havrix Aimmugen Vaqta Bio-Hep B Hepacure Biken-HB Meinyu Engerix B Avaxim Invivac FluMist Rota-Shield Rotarix
 Rotateq Ervevax Varivax Xostavax Bilive reference I 231564 I 215443 I 165805 DNP 04 ARMC 33 I 115091 DNP 12 DNP 15 DNP 14 DNP 10 DNP 10 I 125561 ARMC 39 ARMC 35 ARMC 33 ARMC 34 ARMC 25 ARMC 33 ARMC 32 ARMC 30 ARMC 23 ARMC 35 ARMC 35 I 091119 ARMC 38 ARMC 32 ARMC 27 ARMC 39 DNP 19 I 157373 ARMC 30 ARMC 24 I 277341 ARMC 31 ARMC 32 ARMC 29 ARMC 30 DNP 15 ARMC 31 DNP 15 ARMC 28 ARMC 23 ARMC 35 ARMC 39 I 310829 ARMC 34 ARMC 39 ARMC 32 ARMC 36 ARMC 33 ARMC 32 ARMC 31 DNP 19 I 230590 DNP 19 I 308662 DNP 07 I 334416 DNP 19 DNP 06 DNP 09 DNP 10 DNP 14 DNP 14 DNP 07 DNP 11 I 137797 DNP 10 I 391186 ARMC 39 DNP 12 DNP 18 I 313952 I 115078 DNP 09 I 330188 DNP 19 page source B B B B B B B B B B B B ND ND S S S S S S S S/NM S* S* S* S* S* S* S* S* S* S* S* S* S* S* S* S* S* S* S* S* S*/NM S*/NM S*/NM S*/NM S*/NM S*/NM S*/NM S*/NM S*/NM S*/NM S*/NM V V V V V V V V V V V V V V V V V V V V V V V
 V ReViews Journal of Natural Products, 2007, Vol.
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3 467 Table 5.
Antiparasitic Drugs from 01/1981 to 06/2006 Organized Alphabetically by Generic Name within Source generic name artemisinin ivermectin arteether artemether artenusate eflornithine HCl mefloquine HCI albendazole halofantrine lumefantrine quinfamide atovaquone bulaquine/chloroquine trichomonas vaccine trade name Artemisin Mectizan Artemotil Artemetheri Arinate Ornidyl Fansimef Eskazole Halfan no trade name Amenox Mepron Aablaquin Gynatren year introduced 1987 1987 2000 1987 1987 1990 1985 1982 1988 1987 1984 1992 2000 1986 reference ARMC 23 ARMC 23 DNP 14 I 090712 I 091299 DNP 04 ARMC 21 I 129625 ARMC 24 I 269095 ARMC 20 ARMC 28 DNP 14 I 125543 page 327 336 22 104 329 304 322 326 22 source N N ND ND ND ND ND S S S S S* S* V Table 6.
All Antiinfective (Antibacterial, Fungal, Parasitic, and Viral) Drugs (N ) 230) indication total B N ND S S/NM S* S*/NM V antibacterial 109 antifungal 29 antiparasitic 14 78 antiviral 10 2 64 3 5 2 1 12 23 22 4 7 total percentage 13 230 12 100.0 5.7 5.2 32.3 24.5 74 56 3 1 4 2.2 2 20 22 9.6 1 12 12 4.8 11 1 25 37 15.7 Table 7.
Small Molecule Antiinfective (Antibacterial, Fungal, Parasitic, and Viral) Drugs (N ) 180) indication total antibacterial antifungal antiparasitic antiviral 98 29 13 41 N 10 2 ND 64 3 5 2 S 23 22 4 7 total percentage 180 100.0 12 6.7 74 41.1 56 31.1 S/NM S* S*/NM 3 1 4 2.8 2 20 22 12.2 1 12 11 6.1 ¥ Sources of all NCEs: Where four or more drugs were approved per medical indication (Table 1) ¥ Sources of Small Molecule NCEs: All subdivisions (Figure 3) ¥ Sources of Small Molecule NCEs: By source/year (Figure 4) ¥ Antibacterial Drugs: Generic and trade names, year, reference, and source (Table 2) ¥ Antifungal Drugs: Generic and trade names, year, reference, and source (Table 3) ¥ Antiviral Drugs: Generic and trade names, year, reference, and source (Table 4) ¥ Antiparasitic Drugs: Generic and trade names, year, reference, and source (Table 5) ¥ Antiinfective Drugs: All molecules, source, and numbers (Table 6) ¥ Antiinfective Drugs: Small molecules, source, and numbers (Table 7) ¥ Anticancer Drugs: Generic and trade names, year, reference, and source (Table 8) ¥ All Anticancer Drugs: Generic names, reference, and source (Figures 5-7; and (1940s-06/2006) Table 9) ¥ Antidiabetic Drugs: Generic and trade names, year, reference, and source (Table 10) The extensive data sets shown in the figures and tables referred to above highlight the continuing role that natural products and structures derived from or related to natural products from all sources have played and continue to play in the development of the current
 therapeutic armamentarium of the physician.
Inspection of the data shows this continued important role for natural products in spite of the current low level of natural products-based drug discovery programs in major pharmaceutical houses.

Inspection of the rate of NCE approvals as shown in Figure 2 demonstrates that the natural products field is still producing or is involved in 50% of all small molecules in the years 2000-2006 and that a significant number of NCEs are biologicals or vaccines (83 of 264, or 31.4%).
This is so in spite of many years of work by the pharmaceutical industry devoted to high-throughput screening of predominately combinatorial chemistry products and that the time period chosen should have provided a sufficient time span for combinatorial chemistry work from the late 1980s onward to have produced approved NCEs.
Overall, of the 1184 NCEs covering all diseases/countries/sources in the years 01/1981-06/2006, and using the “NM” classifications introduced in our 2003 review,1,2 30% were synthetic in origin, thus demonstrating the influence of “other than formal synthetics” on drug discovery and approval (Figure 1).
Inspection of Table 1 demonstrates that, overall, the major disease areas that have been investigated (in terms of numbers of drugs approved) in the pharmaceutical industry continue to be infectious diseases (microbial, parasitic, and viral), cancer, antihypertensives, and antiinflammatory indications, all with over 50 approved drug therapies.
It should be noted, however, that numbers of approved drugs/disease do not correlate with the “value” as measured by sales, since the best selling drug of all is atorvastin, a hypocholesterolemic descended directly from a natural product, which sold over $11 billion in 2004 and is at or above this level even today.

The major category by far is that of antiinfectives including antiviral vaccines, with 230 (22.8%) of the total (1010 for indications g 4) falling into this one major human disease area.
On further analyses (Tables 6 and 7), the influence of biologicals and vaccines in this disease complex is such that only a little over 30% are synthetic in origin.

If one considers only small molecules (reducing the total by 50 to 180; Table 10), then the synthetic figure goes up to 31.1%, marginally greater than in our previous report.2 As reported previously,1,2 these synthetic drugs actually tend to be of two basic chemotypes, the azole-based antifungals and the quinolone-based antibacterials.
Four small molecule drugs were approved in the antibacterial area from 01/2003 to 06/2006.

These included daptomycin (N, 5) from Cubist, a lipopeptide whose biosynthetic cluster has been successfully cloned and expressed by investigators associated with Cubist.71 Wyeth had their modified tetracycline derivative, tigecy- cline, approved (ND, 6), a drug designed to overcome the tet resistance pump in pathogenic bacteria, and another carbapenem (ND) and a quinolone (S) were also approved in this time frame.
In the antifungal area, of the five drugs approved, four were azoles (S) and the echinocandin derivative, anidulofungin (ND), was approved for use in the U.S. in early 2006.

In the antiviral area, seven drugs were approved for HIV treatment (1 ND, 1 S*, 5 S*/ NM).

It is interesting that the one ND, enfuvirtide, though listed in most literature as a synthetic, is actually the “end-capped” 36- 468 Journal of Natural Products, 2007, Vol.

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3 ReViews Table 8.
Anticancer Drugs from 01/1981-06/2006 Organized Alphabetically by Generic Name within Source generic name H-101 alemtuzumab bevacizumab celmoleukin cetuximab denileukin diftitox ibritumomab interferon alfa2a interferon, gamma-1a interleukin-2 mobenakin pegaspargase rituximab tasonermin teceleukin tositumomab trastuzumab aclarubicin angiotensin II arglabin masoprocol paclitaxel paclitaxel nanoparticles pentostatin peplomycin solamargines alitretinoin amrubicin HCl belotecan hydrochloride cladribine cytarabine ocfosfate docetaxel elliptinium acetate epirubicin HCI etoposide phosphateb exemestane formestane fulvestrant gemtuzumab ozogamicin hexyl aminolevulinate idarubicin hydrochloride irinotecan hydrochloride miltefosine pirarubicin talaporfin sodium topotecan HCl triptorelin valrubicin vapreotide acetate vinorelbine zinostatin stimalamer aminoglutethimide amsacrine arsenic trioxide bisantrene hydrochloride carboplatin flutamide fotemustine heptaplatin/SK-2053R lobaplatin lonidamine nedaplatin nilutamide oxaliplatin porfimer sodium ranimustine sobuzoxane sorafenib anastrozole bicalutamide bortezomib camostat mesylate erlotinib hydrochloride fadrozole HCl gefitinib imatinib mesilate letrazole trade name none givena Campath Avastin Celeuk Erbitux Ontak Zevalin Roferon-A Biogamma Proleukin Octin Oncaspar Rituxan Beromun Imumace Bexxar Herceptin Aclacin Delivert none givena Actinex Taxol Abraxane Nipent Pepleo Curaderm Panretin Calsed Camtobell Leustatin Starsaid Taxotere Celiptium Farmorubicin Etopophos Aromasin
 Lentaron Faslodex Mylotarg Hexvix Zavedos Campto Miltex Pinorubicin Laserphyrin Hycamptin Decapeptyl Valstar Docrised Navelbine Smancs Cytadren Amsakrin Trisenox Zantrene Paraplatin Drogenil Muphoran Sunpla Lobaplatin Doridamina Aqupla Anadron Eloxatin Photofrin Cymerine Parazolin Nexavar Arimidex Casodex Velcade Foipan Tarceva Afema Iressa Gleevec Femara year introduced 2005 2001 2004 1992 2003 1999 2002 1986 1992 1989 1999 1994 1997 1999 1992 2003 1998 1981 1994 1999 1992 1993 2005 1992 1981 1989 1999 2002
reference DNP 19 DNP 15 ARMC 40 DNP 06 ARMC 39 ARMC 35 ARMC 38 I 204503 ARMC 28 ARMC 25 ARMC 35 ARMC 30 DNP 11 ARMC 35 DNP 06 ARMC 39 DNP 12 I 090013 ARMC 30 ARMC 35 ARMC 28 ARMC 29 DNP 19 ARMC 28 I 090889 DNP 03 ARMC 35 ARMC 38 ARMC 40 ARMC 29 ARMC 29 ARMC 31 I 091123 ARMC 20 DNP 10 DNP 13 ARMC 29 ARMC 38 DNP 14 I 300211 ARMC 26 ARMC 30 ARMC 29 ARMC 24 ARMC 40 ARMC 32 I 090485 ARMC 35 I 135014 ARMC 25 ARMC 30 I 070408 ARMC 23 DNP 14 ARMC 26 ARMC 22 ARMC 19 ARMC 25 ARMC 35 DNP 12 ARMC 23 ARMC 31 ARMC 23 ARMC 32 ARMC 29 ARMC 23 ARMC 30 DNP 19 ARMC 31 ARMC 31 ARMC 39 ARMC 21 ARMC 40 ARMC 31 ARMC 38 DNP 15 ARMC 32 page source B B B B B B B B B B B B B B B B B N N N N N N N N N ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND S S S S S S S S S S S S S S S S S S/NM S/NM S/NM S/NM S/NM S/NM S/NM S/NM S/NM ReViews Table 8.
Continued generic name sunitinib malate temoporfin toremifene zoledronic acid azacytidine capecitabine carmofur clofarabine decitabine doxifluridine enocitabine fludarabine phosphate gemcitabine HCl mitoxantrone HCI nelarabine abarelix bexarotene pemetrexed disodium raltitrexed tamibarotene temozolomide bcg live melanoma theraccine Journal of Natural Products, 2007, Vol.

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3 469 trade name Sutent Foscan Fareston Zometa Vidaza Xeloda Mifurol Clolar Dacogen Furtulon Sunrabin Fludara Gemzar Novantrone Arranon Plenaxis Targretine Alimta Tomudex Amnoid Temodal TheraCys Melacine year introduced 2006 2002 1989 2000 2004 1998 1981 2005 2006 1987 1983 1991 1995 1984 2005 2004 2000 2004 1996 2005 1999 1990 2001 reference I 309144 I 158118 ARMC 25 DNP 14 ARMC 40 ARMC 34 I 091100 DNP 19 I 125366 ARMC 23 ARMC 19 ARMC 27 ARMC 31 ARMC 20 DNP 19 ARMC 40 DNP 14 ARMC 40 ARMC 32 DNP 19 ARMC 35 DNP 04 DNP 15 page 319 24 447 319 44 332 318 327 344 321 45 446 23 463 315 45 350 104 38 source S/NM S/NM S/NM S S* S* S* S* S* S* S* S* S* S* S* S*/NM S*/NM S*/NM S*/NM S*/NM S*/NM V V a No trade name given in the original report nor in the Prous Integrity database.
b A prodrug of etoposide.
residue peptide that corresponds to residues 643-678 of the HIV-1 transmembrane protein gp41 and blocks viral fusion with the cell.72 In addition to this novel mechanism, four new HIV protease inhibitors were approved; all were peptidomimetics imitating the peptide substrate, and the latest one, darunavir (7), actually has the hydroxyethyl isostere that was first identified in the microbial aspartic protease inhibitor pepstatin and incorporated in the base structure of crixivan (see discussion by Yang et al.73).
It should be noted that the percentages used in the following overall analyses do not always agree with those in the later tables, as all sources, which include B and V categorized drugs, and all indications are included in the percentage figures used in the analyses.

Much fuller details are given in the Supporting Information in the form of an Excel XP spreadsheet.
As we reported in our earlier analyses,1,2 there are still significant therapeutic classes where the available drugs are totally synthetic at the present time.

These include antihistamines, diuretics, and hypnotics for indications with four or more approved drugs (cf.

Table 1).

There are a substantial number of indications where there are three or less drugs that are also totally synthetic.
Because of our introduction of the “NM” subcategory, indications such as antidepressants and cardiotonics now have substantial numbers that, although formally “S”, now fall into the “S/NM” subcategory.

From inspection of Tables 1-4 and 8 and the Excel XP spreadsheet, the following points can be made in addition to the digest on antiinfectives given in Tables 6 and 7.
In the antibacterial area (Table 2), as found previously, the vast majority of the 98 small molecule NCEs are N (10; 10.2%), ND (64; 65.3%), or S*/ NM (1; 1%), amounting to 75 in total, or 76.5% of the whole, with the remainder (S) being predominately quinolones.

In the antifungal area (Table 3), the roles of the small molecules (n ) 28) are reversed, with the great majority being S (22; 78.6%) and S/NM (3; 10.7%), with the remainder being ND (3; 10.7%).
In the antiviral area (Table 4), the situation is somewhat different, with a large number of vaccines (n ) 25) now added to this category.

If we consider only small molecules, the anti-HIV drugs being approved are based mainly on nucleoside structures (S*) or on peptidomimetics (S* and S/NM), and drugs against other viral diseases also fall into these categories.
Thus, one can see that of the 42 small molecule approved antiviral agents, the relevant figures are ND (2; 4.8%), S* and S*/NM categories (32; 76.2%), with the remainder falling into either S (7; 16.7%) or S/NM (1; 2.4%).

We have also identified the antiparasitic drugs that have been approved over the years (Table 5) and point out that of the 14 small molecule drugs, only four are synthetic (28.5%) and of the rest, three are artemisinin derivatives.
What is of interest with this base structure is that, in addition to their known antimalarial activities, compounds based on this structure are demonstrating activity as antitumor agents.74 With anticancer drugs (Table 8), where in the time frame covered (01/1981-06/2006) there were 100 NCEs in toto, the number of nonbiologicals was 81 (81%).
These small molecules could be divided as follows (using 81 ) 100%) into N (9; 11.1%), ND (25; 30.9%), S (18; 22.2%), S/NM (12; 14.8%), S* (11; 13.6%), and S*/NM (6; 7.4%).

Thus, using our criteria, only 22.2% of the total number of anticancer drugs were classifiable into the S (synthetic) category.

Expressed as a proportion of the nonbiologicals/vaccines, then 63 of 81 (77.8%) were either natural products per se or were based thereon, or mimicked natural products in one form or another.
In this current review, we have continued as in our previous contribution (2003)2 to reassess the influence of natural products and their mimics as leads to anticancer drugs.

By using data from the FDA listings of antitumor drugs, coupled with our previous data sources and with help from Japanese colleagues, we have been able to identify the years in which all but 18 of the 175 drugs we have listed in Table 9 were approved.
We have identified these other 18 agents by inspection of three time-relevant textbooks on antitumor treatment,51,75,76 and these were added to the overall listings using the lead authors’ names as the source citation.
Inspection of Figures 5-7 and Table 9 shows that, over the whole category of anticancer drugs effectively available to the West and Japan, the 175 available agents can be categorized as follows: B (18; 10%), N (25; 14%), ND (48; 28%), S (42; 24%), S/NM (14; 8%), S* (20; 11%), S*/NM (6; 4%), and V (2; 1%).

If one removes the biologicals and vaccines, reducing the overall number to 155 (100%), the number of naturally inspired agents (i.e., N, ND, S/NM, S*, S*/NM) is 113 (72.9%).
It should be noted that these 155 agents do not include some of the earlier drugs that were really immuno- 470 Journal of Natural Products, 2007, Vol.

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3 ReViews Table 9.
All Anticancer Drugs (1940s-07/2006)a Organized Alphabetically by Generic Name within Source generic name H-101 aldesleukin alemtuzumab bevacizumab celmoleukin cetuximab denileukin diftitox interferon alfa2a interferon alfa2b interferon, gamma-1a interleukin-2 mobenakin pegaspargase rituximab tasonermin teceleukin tositumomab trastuzumab aclarubicin actinomycin D angiotensin II arglabin asparaginase bleomycin carzinophilin chromomycin A3 daunomycin doxorubicin leucovorin masoprocol mithramycin mitomycin C neocarzinostatin paclitaxel palictaxel nanoparticles pentostatin peplomycin sarkomycin solamargine (aka BEC) streptozocin testosterone vinblastine vincristine alitretinoin amrubicin HCl belotecan hydrocholoride calusterone cladribine cytarabine ocfosfate dexamethasone docetaxel dromostanolone elliptinium acetate epirubicin HCI estramustine ethinyl estradiol etoposide exemestane fluoxymesterone formestane fosfestrol fulvestrant gemtuzumab ozogamicin goserelin acetate hexyl aminolevulinate histrelin hydroxyprogesterone idarubicin hydrochloride irinotecan hydrochloride leuprolide medroxyprogesterone acetate megesterol acetate methylprednisolone methyltestosterone miltefosine mitobronitol nadrolone phenylpropionate year introduced pre-1977 pre-1970 1965 1963 1999 2002 2004 1973 1993 1993 1958 1995 1961 1983 1984 1980
 pre-1970 1980 1999 pre-1970 1993 pre-1977 2002 2000 1987 2004 2004 pre-1970 1990 1994 1984 1958 1971 1955 1974 1993 1979 1959 reference DNP 19 ARMC 25 DNP 15 ARMC 40 DNP 06 ARMC 39 ARMC 35 I 204503 I 165805 ARMC 28 ARMC 25 ARMC 35 ARMC 30 DNP 11 ARMC 35 DNP 06 ARMC 39 DNP 12 I 090013 FDA ARMC 30 ARMC 35 FDA FDA Japan Antibiotics Japan Antibiotics FDA FDA FDA ARMC 28 FDA FDA Japan Antibiotics ARMC 29 DNP 19 ARMC 28 I 090889 FDA DNP 03 FDA FDA ARMC 35 ARMC 38 ARMC 40 FDA ARMC 29 ARMC 29 FDA ARMC 31 FDA I 091123 ARMC 20 FDA FDA DNP 13 ARMC 29 ARMC 38 DNP 14 ARMC 23 I 300211 I 109865 ARMC 26 ARMC 30 ARMC 20 FDA FDA FDA FDA ARMC 29 FDA FDA page source ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ReViews Table 9.
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3 471 generic name year introduced reference norethindrone acetate pirarubicin prednisolone prednisone teniposide testolactone topotecan HCl triamcinolone triptorelin valrubicin vapreotide acetate vindesine vinorelbine zinostatin stimalamer amsacrine arsenic trioxide bisantrene hydrochloride busulfan carboplatin carmustine (BCNU) chlorambucil chlortrianisene cis-diamminedichloroplatinum cyclophosphamide dacarbazine diethylstilbestrol flutamide fotemustine heptaplatin/SK-2053R hexamethylmelamine hydroxyurea ifosfamide lenalidomide levamisole lobaplatin lomustine (CCNU) lonidamine mechlorethanamine melphalan mitotane nedaplatin nilutamide nimustine hydrochloride oxaliplatin pamidronate pipobroman porfimer sodium procarbazine ranimustine razoxane semustine (MCCNU) sobuzoxane sorafenib mesylate thiotepa triethylenemelamine zoledronic acid anastrozole bicalutamide bortezomib camostat mesylate dasatiniba erlotinib hydrochloride fadrozole HCl gefitinib imatinib mesilate letrozole nafoxidine sunitinib maleate tamoxifen toremifene aminoglutethimide azacytidine capecitabine carmofur clofarabine pre-1977 1988 pre-1977 pre-1970 1967 1969 1996 1958 1986 1999 2003 1979 1989 1994 1987 2000 1990 1954 1986 1977 1956 pre-1981 1979 1957 1975 pre-1970 1983 1989 1999 1979 1968 1976 2005 pre-1981 1998 1976 1987 1958 1961 1970 1995 1987 pre-1981 1996 1987 1966 1993 1969 1987 pre-1977 pre-1977 1994 2005 1959 pre-1981 2000 1995 1995 2003 1985 2006 2004 1995 2002 2001 1996 pre-1977 2006 1973 1989 1981 pre-1977 1998 1981 2005 ARMC 24 FDA
 FDA ARMC 32 FDA I 090485 ARMC 35 I 135014 FDA ARMC 25 ARMC 30 ARMC 23 DNP 14 ARMC 26 FDA ARMC 22 FDA FDA BOYD FDA FDA FDA ARMC 19 ARMC 25 ARMC 35 FDA FDA FDA DNP 19 Boyd DNP 12 FDA ARMC 23 FDA FDA FDA ARMC 31 ARMC 23 Boyd ARMC 32 ARMC 23 FDA ARMC 29 FDA ARMC 23 ARMC 30 DNP 19 FDA Boyd DNP 14 ARMC 31 ARMC 31 ARMC 39 ARMC 21 I 365055 ARMC 40 ARMC 31 ARMC 38 DNP 15 ARMC 32 I 309144 FDA ARMC 25 319 FDA ARMC 34 FDA DNP 19 page source ND ND ND ND ND ND ND ND ND ND ND ND ND ND S/NM S/NM S/NM S/NM S/NM S/NM S/NM S/NM S/NM S/NM S/NM S/NM S/NM S/NM S* S* S* S* S* 472 Journal of Natural Products, 2007, Vol.
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3 Table 9.
Continued generic name cytosine arabinoside decitabine doxifluridine enocitabine floxuridine fludarabine phosphate fluorouracil ftorafur gemcitabine HCl mercaptopurine methotrexate mitoxantrone HCI nelarabine thioguanine uracil mustard abarelix bexarotene pemetrexed raltitrexed tamibarotene temozolomide bcg live melanoma theraccine year introduced 1969 2006 1987 1983 1971 1991 1962 1972 1995 1953 1954 1984 2005 1966 1966 2004 2000 2004 1996 2005 1999 1990 2001 reference FDA I 125366 ARMC 23 ARMC 19 FDA ARMC 27 FDA FDA ARMC 31 FDA FDA ARMC 20 DNP 19 FDA FDA ARMC 40 DNP 14 ARMC 40 ARMC 32 DNP 19 ARMC 35 DNP 04 DNP 15 a One extra drug added, approved June 28, 2006, launched July 3, 2006.
ReViews source S* S* S* S* S* S* S* S* S* S* S* S* S* S* S* S*/NM S*/NM S*/NM S*/NM S*/NM S*/NM V V page 332 318 327 344 321 45 446 23 463 315 45 350 104 38 Figure 1.

All new chemical entities, 01/1981-06/2006, by source (N ) 1184).

or hematologic stimulants.

Etoposide phosphate is not included in this count, as it is a prodrug of etoposide, though it was included in our last review as an approved NCE.
We have however included paclitaxel nanoparticles, as this is not just a salt form but is a novel form of the agent ensuring much better water solubility.

In our earlier papers, the number of nonsynthetic antitumor agents was 62% for other than biologicals/vaccines, without an “NM” subcategory.

The corresponding figure obtained by removing the NM subcategory in this analysis is 64%.
Thus, the proportion has remained similar in spite of some reassignments of sources and the expansion of combinatorial chemistry techniques.

As mentioned earlier, the first and only de noVo combinatorial drug that we have been able to identify was approved by the FDA in 2005 under the generic name of sorafenib mesylate (1) for the treatment of advanced renal cancer.
A major general class of drugs that was not commented on in any detail in our earlier papers is the class that is directed toward the treatment of diabetes, both types I and II (Table 10; n ) 32).
These drugs include a significant number of biologics based upon varying modifications of insulin produced in general by biotech- nological means (B, 18; 56.3%).50 In addition to these well-known the class also includes a very interesting compound agents, (approved by the FDA in 2005) that is assigned to the ND class (extenatide or Byetta).

This is the first in a new class of therapeutic agents known as incretin mimetics.
The drug exhibits glucose- lowering activity similar to the naturally occurring incretin hormone glucagon-like peptide-1 (GLP-1), but is a 39-residue peptide based upon one of the peptide venoms of the Gila monster, Heloderma suspectum.77 Discussion As alluded to in our previous review, the decline or leveling of the output of the R&D programs of the pharmaceutical companies has continued, with the number of drugs of all types dropping in 2003 to 35 launches, including 13 in the B/V categories, and reaching a nadir in 2004, when only 25 were launches and 6 of these fell into the B/V categories.
There was a significant upswing in 2005 with 54 launches, but 20 of these were in the B/V categories, leaving 34 small molecules.

In the first 6 months of 2006, of the 22 launches, 9 were B/V.

Although combinatorial chemistry continues to play a major role in the drug development process, as mentioned earlier, is noteworthy that the trend toward the synthesis of complex natural product-like libraries has continued.
As was eloquently stated by Danishefsky in 2002, “a small collection of smart compounds may be more Valuable than a much larger hodgepodge collection mindlessly assembled”.78 Recently he and a coauthor restated this theme:79 it ReViews Journal of Natural Products, 2007, Vol.

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3 473 Figure 2.

All new chemical entities organized by source/year (N ) 1184).

Figure 3.

All small molecule new chemical entities, 01/1981-06/2006, by Source (N ) 974).
In summary, we haVe presented seVeral happy experiences in the course of our program directed toward bringing to bear nature’s treasures of small molecule natural products on the momentous challenge of human neurodegeneratiVe diseases.

While biological results are now being accumulated for sys- tematic disclosure, it is already clear that there is considerable in compounds obtained through plowing in the potential landscape of natural products.
Particularly impressiVe are those compounds that are obtained through diVerted total synthesis, i.e., through methodology, which was redirected from the original (and realized) goal of total synthesis, to encompass otherwise unaVailable congeners.

We are confident that the program will lead, minimally, to compounds that are deserVing of serious preclinical follow-up.
At the broader leVel, we note that this program will confirm once again (if further confirma- tion is, indeed, necessary) the extraordinary adVantages of small molecule natural products as sources of agents, which interject themselVes in a helpful way in Various physiological processes.
We close with the hope and expectation that enterprising and hearty organic chemists will not pass up the unique head start that natural products proVide in the quest for new agents and new directions in medicinal discoVery.
We would chance to that eVen as the currently fashionable “telephone predict directory” mode of research is subjected to much oVerdue scrutiny and performance-based assessment, organic chemists in concert with biologists and eVen clinicians will be enjoying as well as exploiting the rich troVes proVided by nature’s small molecules.

474 Journal of Natural Products, 2007, Vol.

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3 ReViews Figure 4.

Small molecule new chemical entities organized by source/year (N ) 974).

Figure 5.
Figure 5.

All available anticancer drugs, 1940s-06/2006, by source (N ) 175).

A rapid analysis of the entities approved from 2003 to 2006 (the full data set is available as an Excel spreadsheet in the Supporting Information) indicated that there were significant numbers of antitumor, antibacterial, and antifungal agents approved as men- tioned above.

This time frame also saw two very important approvals, both of which were natural products.
The first was the approval by the FDA, after a long series of trials and discussions, of the cone snail toxin known as Prialt, which is the first “direct from the sea” entity to become a licensed pharmaceutical.80,81 Although one can argue (as we have on other occasions) that the discovery of the arabinose nucleosides by Bergmann in the 1950s was the driving force behind Ara-A, Ara-C, AZT, etc., this is the first direct transition from marine invertebrate to man.
Also in the the botanical preparation Hemoxin82,83 was middle of 2006, approved in Nigeria following demonstration of efficacy in clinical trials as a treatment for sickle cell anemia.

This is a mix of plants that came from native healer information and thus can be classified as a “true ethnobotanical preparation”.
In this paper, as we stated in 2003,2 we have again demonstrated that natural products play a dominant role in the discovery of leads for the development of drugs for the treatment of human diseases.

Some have argued (though not in press, only in personal conversa- tions at various fora) that the introduction of categories such as S/NM and S*/NM is an overstatement of the role played by natural products in the drug discovery process.
On the contrary, we would argue that these further serve to illustrate the inspiration provided by Nature to receptive organic chemists in devising ingenious syntheses of structural mimics to compete with Mother Nature’s ReViews Journal of Natural Products, 2007, Vol.

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3 475 Figure 6.

Approved anticancer agents, organized by source/year (known dates for 157).

Table 10.
Antidiabetic Drugs from 01/1981 to 06/2006 Organized Alphabetically by Generic Name within Source generic name trade name year introduced biphasic porcine insulin hu neutral insulin human insulin Zn suspension human insulin zinc suspension human neutral insulin insulin aspart insulin aspart/IA protamine insulin determir insulin glargine insulin glulisine insulin lispro isophane insulin mecasermin oral insulin porcine isophane insulin porcine neutral insulin pulmonary insulin soluble insulin voglibose acarbose extenatide miglitol triproamylin acetate glimepiride mitiglinide calcium hydrate pioglitazone NCl repaglinide epalrestat rosiglitazone maleate tolrestat troglitazone nateglinide Pork Mixtard 30 Insuman Humulin L Humulin Zn Novolin R NovoRapid NovoMix 30 Levemir Lantus Apidra Humalog Humulin N Somazon Oral-lyn Pork Insulatard Pork Actrapid Exubera Velosulin BR Basen Glucobay Byetta Diastabol Normylin Amaryl Glufast Actos Prandin Kinedak Avandia Alredase Rezulin Starsis reference I 303034 I 255451 I 302828 I 091584 I 182551 DNP 13 DNP 15 DNP 18 DNP 14 DNP 19 ARMC 32 I 091583 DNP 08 DNP 19 I 302757 I 302749 I 229896 I 091581 ARMC 30 DNP 03 DNP 19 ARMC 34 DNP 19 ARMC 31 ARMC 40 ARMC 35 ARMC 34 ARMC 28 ARMC 35 ARMC 25 ARMC 33 ARMC 35 page source B B B B B B B B B B B B B B B B B B N ND ND ND ND S S S S S/NM S/NM S/NM S/NM S* 41 34 27 19 39 310 28 39 313
 23 40 325 40 344 460 346 329 330 348 319 344 344 longstanding substrates.
Even discounting these categories, the continuing and overwhelming contribution of natural products to the expansion of the chemotherapeutic armamentarium is clearly evident, and as we stated in our earlier papers, much of Nature’s “treasure trove of small molecules” remains to be explored, particularly from the marine and microbial environments.

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(7) Reayi, A.; Arya, P. Curr.

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Figure 7.

Approved anticancer agents, organized by source/year (unknown dates for 18).

From the perspective of microbes and their role(s) as sources of novel bioactive entities, the recent work that has been reported by a variety of investigators as to the potential of these organisms needs to be widely disseminated.
Over the last few years, it has become obvious from analyses of the published (and, to some extent, unpublished) genomic sequences of a variety of microbes that there are at least a dozen potential biosynthetic clusters in each organism in certain well-publicized cases, over 30 such surveyed and, groupings.84-92 In the marine environment the interplay of these two sources, as exemplified by the recent review by Newman and Hill,93 leaves no doubt that a host of novel, bioactive chemotypes await discovery from both terrestrial and marine sources.
In this respect it should be noted that in the last year or so there has been a very significant series of findings where the well-known antitumor agents camptothecin94 and podophyllotoxin95 and vinc- ristine96 have now been produced by fermentation of endophytic fungi, isolated from the producing plants.
The usual argument that these are artifacts because of the inability to produce large quantities by regular fermentation processes has been shown to be specious by the work by Bok et al.84 with Aspergillus nidulans.

This work demonstrated that one has to be able to find the “genetic on switch” to be able to obtain expression of such clusters outside of the host.
In addition to these papers the reader’s attention is also drawn to the recent excellent review article by Gunatilaka97 on this subject, which gives an excellent overview of the numbers of materials so far discovered from these sources.

As a result, investigators need to consider all possible routes to novel agents.
To us, a multidisciplinary approach to drug discovery, involving the generation of truly novel molecular diversity from natural product sources, combined with total and combinatorial synthetic methodologies, and including the manipulation of biosynthetic pathways (so-called combinatorial biosynthesis), provides the best solution to the current productivity crisis facing the scientific community engaged in drug discovery and development.
Once more, as we stated in our 2003 review,2 we strongly advocate expanding, not decreasing, the exploration of Nature as a source of novel active agents that may serve as the leads and scaffolds for elaboration into desperately needed efficacious drugs for a multitude of disease indications.

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