CC-1065 and the duocarmycins: unraveling the keys to a new class of naturally derived DNA alkylating agents.

Abstract

Key studies defining the DNA alkylation properties and selectivity of a new class of exceptionally potent, naturally occurring antitumor antibiotics including CC-1065, duocarmycin A, and duocarmycin SA are reviewed. Recent studies conducted with synthetic agents containing deep-seated structural changes and the unnatural enantiomers of the natural products and related analogs have defined the structural basis for the sequence-selective alkylation of duplex DNA and fundamental relationships between chemical structure, functional reactivity, and biological properties. The agents undergo a reversible, stereoelectronicaily controlled adenine-N3

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

“…N ‐Boc‐DSA was found to be a substantially less efficient (ca. 10 4  times) DNA alkylator, with a less strict selectivity profile than the parent natural product (SA), and with both enantiomers showing the same site reactivity profile 52a. The latter property was also unusual, but a natural consequence of the diastereomeric relationship of the adducts.…”

Preclinical Profile of the HER2-Targeting ADC SYD983/SYD985: Introduction of a New Duocarmycin-Based Linker-Drug Platform

“…This class of compounds binds to the minor groove in DNA and subsequently alkylates specific adenine residues via ring opening of their cyclopropyl group, which eventually leads to cell death (11). Several synthetic duocarmycin analogs have been taken into development, but they all failed in the clinic or before as a consequence of a limited TI (17)(18)(19).…”

“…A new-generation platform of LDs has been developed on the basis of chemically synthesized duocarmycins which are DNA-alkylating cytotoxic drugs (10,11) that induce cell death in both dividing and nondividing cells. The aim is to improve the currently used LDs and increase the TI that can be obtained with ADCs based on these new LDs as compared with that of the earlier generation ADCs.…”

Evaluation of a reductively activated duocarmycin prodrug against murine and human solid cancers

“…previously, we characterized prodrugs of seco-CBI-indole 2 (CBI-indole 2 ) designed to be activated in hypoxic tumor microenvironments, wherein the tumor maintains higher concentrations of "reducing" nucleophiles capable of preferentially releasing the free drug by nucleophilic attack on a weak N-O bond. Of these prodrugs, BocNhO-CBI-indole 2 (BocNhO) surpassed the efficacy of the free drug, CBI-indole 2 , when examined in vivo in the murine L1210 leukemia model and demonstrated reduced toxicity suggesting a targeted or sustained release in vivo. herein, we further examine the biological activity of the BocNhO prodrug in murine breast cancer, as well as human prostate and lung cancer cell lines, in vitro.…”

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Mechanistically, this selective DNA alkylation is achieved through the forced adoption of a helical conformation upon binding to the minor-groove AT-rich regions of DNA, which disrupts the stabilizing vinylogous amide and activates the cyclopropane for nucleophilic attack. 19,20 These natural products are not clinically viable due to either severe adverse events, including lethal hepatotoxicity and extreme myelotoxicity, or a lack of in vivo activity.…”