Analogs of sandramycin (1) are synthesized and shown to have cytoxicity against various tumor cell types. The relative cytotoxic properties of the sandramycin analogs are approximately parallel tp their relative DNA binding affinities. An exception to this generalization is compound (4) which completely the sandramycin chromophore phenol. Although typically 4-10.times. less potent than sandramycin against leukemia cell lines, compound (4) proved to be 1-10,000.times. more potent against melanomas, carcinomas, and adenocarcinomas exhibiting IC.sub.50 values of 1 pM-10 nM. This activity places compound (4) amongst the most potent agents identified to date.

FIELD OF THE INVENTION
 The invention relates to analogs of sandramycin, to the synthesis of
 analogs of sandramycin, and to their use as anti-cancer and anti-HIV
 agents. More particularly, the invention relates to analogs of sandramycin
 having deep-seated structural changes in the chromophore including the
 deletion of key functional groups or core structural elements, to the
 synthesis of these compounds the penultimate introduction of substitution
 chromophores on a key intermediate, and to the use of these compounds
 against various leukemia, melanoma, carinoma, and adenocarcinomas.
 Furthermore, some of the analogs possess the ability to inhibit HIV-1
 reverse transcriptase.
 BACKGROUND
 Sandramycin (1) is a natural product having potent antitumor antibiotic
 activity. Sandramycin has been structurally characterized through
 spectroscopic and chemical degradation studies. Sandramycin constitutes
 one of the newest members of a growing class of cyclic decadepsipeptides
 including luzopeptins A-C and E.sub.2, quinaldopeptin and guinoxapeptins A
 and B which possess potent antitumor, antiviral, and antimicrobial
 activity (FIG. 1; Matson, et al. J. Antibiot. 1989, 42, 1763; Matson et
 al. J. Antibiot. 1993, 46, 162; Ohkuma et al. J. Antibiot. 1980, 33, 1087;
 Tomita et al. J. Antibiot. 1980, 33, 1098; J. Antibiot. 1981, 34, 148;
 Konishi et al. J. Am. Chem. Soc. 1981, 103, 1241; Arnold et al. J. Am.
 Chem. Soc. 1981, 103, 1243; Toda et al. J. Antibiot. 1990, 43, 796).
 Characteristic of this class of agents, sandramycin possesses a two-fold
 axis of symmetry and two heteroaromatic chromophores that results in
 sequence-selective DNA bis-intercalation spanning two base-pairs
 preferentially at 5'-AT sites. In this respect, the agents are
 functionally related to the quinoxaline antitumor antibiotics including
 echinomycin and triostin A which also bind to DNA by bis-intercalation but
 with a substantially different sequence selectivity (5'-CG versus 5'-AT).
 The cytotoxic activity of luzopeptin A and sandramycin has been shown to be
 100-300 times greater than echinomycin and smoothly declines in the series
 with luzopeptin A&gt;B&gt;C. A reverse order of antiviral activity was
 observed with luzopeptin C&gt;B&gt;A in inhibiting human immunodeficiency
 virus (HIV) replication in vitro. Notably, this is observed at
 noncytotoxic concentration for luzopeptin C through inhibition of HIV
 reverse transcriptase (Take et al. J. Antibiot. 1989, 42, 107; Inouye et
 al. J. Antibiot. 1987, 40, 100). The recent disclosure of the
 quinoxapeptins as potent inhibitors of HIV-1 and HIV-2 reverse
 transcriptase that are equally active against two resistant single mutants
 and a double mutant of HIV-1 reverse transcriptase has increased the
 interest in this class of agents especially since they were found not to
 inhibit human DNA polymerase .alpha., .beta., .gamma., and .delta. at
 comparable concentrations (Lingham et al. J. Antibiot. 1996, 49, 253).
 What is needed are analogs of sandramycin having enhanced cytotoxic
 activities against various tumor cell lines and sandramycin analogs having
 inhibitatory activity against reverse transcriptase. Furthermore, what is
 needed are active analogs of sandramycin which can be synthesized from
 economically accessable sources.
 BRIEF SUMMARY OF THE INVENTION
 The invention is directed to sandramycin analogs which possesses unique and
 specific properties against various leukemia, melanoma, carinoma, and
 adenocarcinoma cells. The invention is also directed to analogs having
 inhibitory activity with respect to HIV-1 reverse transcriptase. The
 synthesis of a series of these analogs is carried out by the penultimate
 introduction of substitution chromophores on a key intermediate (23). Each
 analog contains a deep-seated structural change in the chromophore
 including the deletion of key functional groups or core structural
 elements which reveals each functional groups role in the high affinity
 bis-intercalation binding of sandramycin.
 One aspect of the invention is directed to Sandramycin analogs following
 structure:
 ##STR1##
 In the above structure, R.sub.1 is a radical represented by any of the
 following structures:
 ##STR2##
 R.sub.2 is a radical selected from hydrogen, --OH, --OBenzyl, and
 --Omethyl. R.sub.3 is a radical selected from hydrogen, --OMethyl, and
 Methyl. R.sub.4 is a radical selected from hydrogen and --Cl.
 R.sub.5 is a radical selected from hydrogen, --OH, and O-Benzyl.
 R.sub.6 is a radical selected from hydrogen, --OH, and O-Benzyl.
 R.sub.7 is a radical selected from hydrogen, --OH, and O-Benzyl.
 Preferred sandramycin analogs are represented by the following structures:
 ##STR3##
 ##STR4##
 ##STR5##
 ##STR6##
 ##STR7##
 ##STR8##
 Another aspect of the invention is directed to a topical formulation
 comprising a sandramycin analog admixed with a pharmaceutically acceptable
 carrier for treating melanoma. Preferred sandramycin analog are indicated
 above. A preferred topical formulation for treating melanoma employs a
 sandramycin analog is represented by the following structure:
 ##STR9##
 Another aspect of the invention is directed to a method for treating
 melanoma. The method employs the step of applying the above topical
 formulation to the melanoma.