Compositions and methods of use thereof achiral analogues of CC-1065 and duocarmycins

Abstract

The present invention relates to novel achiral seco-analogues of the DNA minor groove and sequence-selective alkylating agents (+)-CC1065 and the duocarmycins, depicted as general class (I), (II), (III), (IV) and (V) wherein X is a good leaving group, such as chloride, a bromide, an iodide, a mesylate, a tosylate, an acetate, a quaternary ammonium moiety, a mercaptan, an alkylsulfoxyl, or an alkylsulfonyl group, preferably either a chloride, a bromide, or an iodide group. R1 is a suitable minor groove binding agent to enhance the interactions of the achiral seco-cyclopropaneindole (CI) or an achiral seco-duocarmycin with specific sequences of DNA. R and R2-R5 are defined in claim 1.

Description

[0001] Related application

[0002] This application is a partial continuation application of US Patent Application 09 / 666,160, which is incorporated herein by reference. Technical field

[0003] The present invention relates to new (+)-CC1065 and duocarmycins achiral seco-analogs and pharmaceutical compositions containing the achiral analogs. (+)-CC1065 and Docamixin achiral analogues are used as anticancer drugs. Background technique

[0004] A class of compounds that have received much attention recently are DNA minor groove binders (1a) that exert their anticancer activity by alkylating specific DNA sequences. Minor groove interaction agents are more attractive than intercalators and major groove binders, because the minor groove is generally only occupied by spine of hydration, and therefore the anticancer drugs are more accessible. In addition, covalent modifications in the minor groove are generally more toxic to cells than their major groove alkylation counterparts, such a...

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