Duocarmycins, are families of a series of natural products with exquisite cytotoxicity originally identified in Streptomyces bacteria in the 1970s. As parent members of a class of potent antitumor antibiotics, Duocarmycins derive their properties through a sequence-selective alkylation of duplex DNA. This class of compounds evolved from natural product cyclopropylindolines, have been widely explored as very potent cytotoxins targeted at the DNA minor groove.
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Duocarmycins contain a cyclopropylpyrroloindolone DNA alkylating functionality and a non-covalently active portion, such as a 5,6,7-trimethoxyindole-2-carbonyl moiety. Duocarmycins derived from common scaffolds, such as Duocarmycin SA, are precursor molecules that contain a phenolic hydroxyl group that is responsible for initiating rearrangement of the pharmacophore to produce a cyclopropane-containing cytotoxin, via a process known as spirocyclisation. The natural Duocarmycin products are produced in the enantiomerically S-configuration at the chloromethane chiral centre. The chiral configuration of the Duocarmycins has been demonstrated to influence both the sequence selectivity of DNA alkylation and the potency. In regard to the latter, the S-enantiomer is 100–1000-fold more potent than the R-enantiomer in generating DNA damage, and synthetic approaches are typically aimed at producing the pure S-configuration for this reason.
Duocarmycin compounds consist of a spirocyclic subunit that bind to the minor groove of AT-rich sequences of DNA. Then, the reactivity of the cyclopropane is enhanced significantly for reaction with adenine-N3 to form a covalent bond, which subsequently causes irreversible alkylation of DNA. This disrupts the nucleic acid architecture and leads to killing of cancer cells through apoptosis.
Duocarmycins are more efficacious in tumor cell killing than tubulin binders, particularly in solid tumors. A Duocarmycin-based ADC (known as SYD985) is currently in Phase III clinical trials for breast cancers. The SYD985 uses a Duocarmycin-derived payload (DUBA), which is O-linked to a self-elimination group designed to undergo spontaneous breakdown after cleavage at an adjacent valine citrulline site by cathepsin B. This elimination releases a seco-DUBA, which undergoes spirocyclisation to an active form. The drug linker is conjugated to the antibody through a thiol-reactive maleimide to cysteines exposed through interchain disulfide bond reductions. SYD985 was effective against patient-derived xenografts with resistance to trastuzumab emtansine.
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