Duocarmycins

Duocarmycins

Catalog Product Name CAS Number Molecular Formula Molecular Weight
BADC-00813 Duocarmycin SA 130288-24-3 C25H23N3O7 477.47 g/mol
BADC-00576 (+)-CBI-CDPI2 128300-15-2 C36H28N6O4 608.65
BADC-00341 Seco-Duocarmycin SA 152785-82-5 C25H24ClN3O7 513.93
BADC-00342 Seco-Duocarmycin MA 1613286-57-9 C34H31ClN4O5 611.09
BADC-00337 Seco-Duocarmycin TM 1142188-60-0 C25H23ClN2O5 466.91
BADC-00588 DC41-SMe 1354787-71-5 C38H36ClN5O4S2 726.31
BADC-00223 Duocarmycin A 118292-34-5 C26H25N3O8 507.49
BADC-00575 (+)-CBI-CDPI1 128300-14-1 C25H20N4O3 424.45
BADC-00605 Duocarmycin TM 157922-77-5 C25H23ClN2O5 466.91
BADC-00614 DC1 169901-27-3 C34H28ClN5O4S 638.14
BADC-00680 DC1-SMe 501666-85-9 C35H30ClN5O4S2 684.23
BADC-00681 DC0-NH2 615538-51-7 C31H24ClN5O3 550.01
BADC-00633 MC-Val-Cit-PAB-duocarmycin 2055896-98-3 C54H65ClN9O9 1019.6
BADC-00865 Mal-PEG4-VC-PAB-DMEA-Seco-Duocarmycin SA 2259318-49-3 C67H87ClN12O21 1431.93 g/mol
BADC-00871 Fmoc-Val-Cit-PAB-Duocarmycin TM C58H60ClN7O10 1050.59 g/mol

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.

Chemical structure

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.

Mechanism of action

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.

Application

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.

References

  1. Uematsu, M.; et al. A five-membered lactone prodrug of CBI-based analogs of the duocarmycins. Tetrahedron Letters, 2015, 56: 3101–3104.
  2. Chavda, S.; et al. A novel achiral seco-cyclopropylpyrido[e]indolone (CPyI) analog of CC-1065 and the duocarmycins: Synthesis, DNA interactions, in vivo anticancer and anti-parasitic evaluation. Bioorg. Med. Chem., 2010, 18: 5016–5024.
* Only for research. Not suitable for any diagnostic or therapeutic use.

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