The utility of organic azides and amine derivatives in medicinal chemistry
Creators: name: Kandikonda, Sureshkumar
Publisher: name: RMIT University
Year: 2024
Subjects: classificationCode: 340401
subject: Biologically active molecules
classificationCode: 340499
subject: Medicinal and biomolecular chemistry not elsewhere classified
classificationCode: 340599
subject: Organic chemistry not elsewhere classified

description: Organic azides and amine derivatives are of great importance in organic synthesis and play a vital role in diverse organic transformations, including the synthesis of various bioactive molecules, drugs and natural products. In Chapter 1 the properties of organic azides, earlier approaches for the synthesis of organic azides and amines from their corresponding alcohols. This chapter also discusses applications of organic azides in different fields, such as synthesis and biological importance of triazoles and non-natural amino acids.<br><br>The alcohol functional group can serves as a potential electrophiles with respect to green chemistry principles. It is not a good leaving group, however activation/protonation of alcoholic oxygen makes it a better leaving group. In Chapter 2 the Zirconium tetrachloride (ZrCl4) catalysed conversion of carbinols into the corresponding azides (direct azidation) with azidotrimethyl silane (TMSN3) in acetonitrile at room temperature in a single step is discussed. This chapter also includes synthesis of novel triazole analogues from diverse azide scaffolds and their antimicrobial studies.<br><br>Triazole drugs are widely used for the treatment of life‐threatening invasive fungal infections in cancer patients. In Chapter 3 the synthesis of new compounds that contain the 1,2,3‐triazole moiety tethered to substituted vanillin or isovanillin is presented. In our synthesis, vanillin and isovanillin were first converted into cyclopentyl/cyclohexyl ethers and subsequently treated with methyl Grignard to give the corresponding carbinols. These carbinols, after reaction with TMSN3 and ZrCl4 gave the corresponding azides. Treatment of these azides with diverse acetylenes under Click chemistry conditions produced the final triazoles. The products were screened for their potential anticancer activity on 60 human-cancer cell lines at a 10 μM dose. With the exception of two triazoles, most others had weak or no activity. The two active compounds exhibited strong inhibitory effects against different cell lines, with the highest inhibition against breast cancer panel. To elucidate the underlying molecular mechanisms involved, the clonogenic potential and anchorage‐independent growth of estrogen-receptor positive (MCF7 and T47D) and estrogen-receptor negative (MDA‐MB‐231 and MDA‐MB‐468) breast cancer cells respectively and the induction of apoptotic pathways were investigated. The results of these biological investigations were also presented.<br><br>Organic allyl azides are a specific class of azides that are intermediates in various organic reactions. They are easily converted into corresponding allylamines that have many applications in the field of medicinal chemistry and for the synthesis of natural products. Allyl alcohols are the readily available starting materials for conversion into corresponding azides. In Chapter 4 the synthesis of various allyl azides from the corresponding aryl vinyl carbinols through a novel rearrangement of the vinyl double bond using a ZrCl4- catalysed conversion of diverse aryl vinyl carbinols with TMSN3 in CH3CN at room temperature is presented. Furthermore, a rare class of non-natural γ4-amino acids with a carbohydrate side chain has been synthesised using this strategy. Non-natural amino acids are unique and they offer advantages over the natural amino acids in the site of specific bioconjugation reactions.<br><br>Earlier research on tryptamines has indicated it they have good activity against a Transient Receptor Potential Vanilloid (TRPV) channel, which led to the design of selective amine derivatives with modifications of the tryptamine side chain. To date, 28 mammalian TRP channels have been characterised. The majority of the TRP channels are non-selective cation channels expressed on the cell membrane, and many of them exhibit high permeability for Ca2+. They moderate sensory functions such as vision, taste transduction, temperature sensation and pheromone signalling as well as homeostatic functions such as divalent cation flux, hormone release and osmoregulation. In Chapter 5 TRPV channel classification, its role in skin, brain and hair in the human body, the drugs so far developed for TRPV3 activity and the synthesis of selected amine derivatives as potential TRPV3 antagonists and their functional assay is presented. Conclusion and future work are briefly summarised in Chapter 6.