Part~I. Evaluation of the noncovalent binding selectivity of the antitumor antibiotic (+)-CC -1065. Part~II. Use of an alternative strategy for generation of singly 5'-phosphorus-32 end-labeled double-stranded DNA for evaluation of the DNA alkylation properties of (+)-CC -1065 functional analogs. Part~III. Evaluation of the antitumor antibiotics, duocarmycins/pyrindamycins, and their functional analogs. Part~IV. An alternative preparation of a key intermediate employed in the synthesis of the left-hand subunit of (+)-CC -1065

Hamideh Zarrinmayeh, Purdue University

Abstract

Full details of the comparative DNA binding properties and cytotoxic activity of CDPI$\sb{\rm n}$ (n = 1-5) and PDE-I$\sb{\rm n}$ (n = 1-3) methyl esters are presented in efforts to establish the structural and functional features of (+)-CC-1065 that contribute to the sequence selectivity of the agent:DNA alkylation. The results of these studies provide sufficient evidence that the sequence selectivity of the (+)-CC-1065 may be attributed to the high affinity and noncovalent binding selectivity of the agent for A-T rich regions of DNA minor groove. An alternative strategy was used for securing substantial quantities of singly $5\sp\prime$-$\sp{32}$P-end-labeled double-stranded DNA. This strategy was employed for examination of the comparative DNA alkylation property of (+)-CC-1065 versus the simple derivatives of the alkylation subunit, CPI. The profile of DNA alkylation by (+)-N-BOC-CPI and (+)-N-acetyl-CPI proved to be less selective and readily distinguished from that of (+)-CC-1065. The simple derivatives of the parent alkylation subunit (CI) of the (+)-CC-1065 left-hand segment showed the DNA alkylation profile similar to those of (+)-N-BOC-CPI and (+)-N-acetyl-CPI. This result suggests that CI constitutes the minimum pharmacophore of the (+)-CC-1065 alkylation subunit. In 1988 a new class of antitumor antibiotics called duocarmycins (A, SA, and C$\sb1$-C$\sb2)$ were isolated from Streptomyces sp. The structural similarities between the duocarmycins and (+)-CC-1065 led us to study the DNA alkylation properties of these agents. The results show that there is a striking similarity in the profile of the duocarmycins DNA alkylation with that of (+)-CC-1065. Functional analogs of duocarmycins, ($\pm$)-seco-CI-TMI and ($\pm$)-CI-TMI, also displayed DNA alkylation profiles similar to those of duocarmycins. This illustrates that ($\pm$)-CI-TMI incorporates the minimum potent pharmacophore of the duocarmycin DNA alkylation subunit and the common pharmacophore of the duocarmycins/CC-1065 alkylation subunits. Full details of the studies on the regiospecificity of the nucleophilic addition to selectively activated p-quinone diimines under the control of base-catalyzed, acid-catalyzed, and Lewis acid-catalyzed are presented. The regioselectivity of the nucleophilic addition to p-quinone diimine 36c under Lewis acid-catalyzed condition, permits an alternative preparation of $N\sp1,N\sp5$-dibenzoyl-5-amino-7-(benzyloxy)-3-methylindole, a key intermediate employed in the synthesis of the left-hand subunit of (+)-CC-1065.

Degree

Ph.D.

Advisors

Boger, Purdue University.

Subject Area

Organic chemistry|Pharmacology

COinS