SYNTHESIS AND STUDY OF RAS K SPECIFIC ANTITUMOR DRUGS

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The potential clinical use of the potent antitumor streptonigrin (20a) and lavendamycin (5) has been precluded because of their toxicity. The long-term objective of this proposal is to determine the factors which control the biological activity of these two related systems so that rational approaches to the design and development of selective drugs can be pursued. Results of previous structure-activity relationship (SAR) studies on partial structures of lavendamycin and streptonigrin are inconclusive compared with the results obtained with the parent molecules. This indicates that the complete molecular structures may have a definite effect on the activity. Thus, the immediate goal of this proposal is to synthesize and perform SAR studies on a series of novel lavendamycin derivatives all possessing the complete parent ring structure. The derivatives will range from the unsubstituted pentacyclic ring to mono, di and trisubstituted derivatives, including those with electron withdrawing and releasing groups at the C-7 position. This study will allow us to clearly identify the minimum potent pharmacophore of the lavendamycin system and to determine the role that the parent skeleton, the quinolinedione reduction potential and each individual substituent plays in the overall activity of the molecule. A total of 19 compounds will be prepared by the Pictet-Spengler condensation of the desired quinolinedione-2-carbaldehydes with tryptamine or tryptophans according to our new and efficient route used in the synthesis of lavendamycin methyl ester. The biological activity of these compounds will be determined on rasK, rasH, 3LL and parent nontransformed (NRKE) cell lines. For more potent selective derivatives an assessment of in vivo activity will also be performed.