ABSTRACT
The duocarmycins belong to a class of agent which has great potential for use in cancer therapy. Their exquisite potency means they are too toxic for systemic use, and targeted approaches are required to unlock their clinical potential. In this study, we have explored seco-OH-chloromethylindoline (CI) duocarmycin-based bioprecursors for their potential for cytochrome P450 (CYP)-mediated cancer cell kill. We report on synthetic and biological explorations of racemic seco-CI-MI, where MI is a 5-methoxy indole motif, and dehydroxylated analogues. We show up to a 10-fold bioactivation of de-OH CI-MI and a fluoro bioprecursor analogue in CYP1A1-transfected cells. Using CYP bactosomes, we also demonstrate that CYP1A2 but not CYP1B1 or CYP3A4 has propensity for potentiating these compounds, indicating preference for CYP1A bioactivation.
Subject(s)
Antineoplastic Agents/pharmacology , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Cytochrome P-450 Enzyme System/metabolism , Duocarmycins/pharmacology , Indoles/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cytochrome P-450 Enzyme Inhibitors/chemical synthesis , Cytochrome P-450 Enzyme Inhibitors/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Duocarmycins/chemical synthesis , Duocarmycins/chemistry , Humans , Indoles/chemical synthesis , Indoles/chemistry , Molecular Structure , Structure-Activity RelationshipABSTRACT
The duocarmycins belong to a class of agent that has fascinated scientists for over four decades. Their exquisite potency, unique mechanism of action, and efficacy in multidrug-resistant tumour models makes them attractive to medicinal chemists and drug hunters. However, despite great advances in fine-tuning biological activity through structure-activity relationship studies (SARS), no duocarmycin-based therapeutic has reached clinical approval. In this review, we provide an overview of the most promising strategies currently used and include both tumour-targeted prodrug approaches and antibody-directed technologies.
Subject(s)
Antineoplastic Agents, Alkylating/pharmacology , Duocarmycins/pharmacology , Neoplasms/drug therapy , Animals , Antibodies/immunology , Antineoplastic Agents, Alkylating/chemistry , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Duocarmycins/administration & dosage , Duocarmycins/chemistry , Humans , Prodrugs , Structure-Activity RelationshipABSTRACT
Solid-phase synthesis allowed the rapid generation of a peptide-drug conjugate. A peptide targeting the Thomsen-Friedenreich antigen (TFα) was conjugated to the alkylating subunit of the potent cytotoxin duocarmycin SA. The compound, containing a cathepsin B cleavable linker, was shown to be active and selective against TFα expressing tumor cell lines.
