RESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Duocarmicinas/farmacologia , Indóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores das Enzimas do Citocromo P-450/síntese química , Inibidores das Enzimas do Citocromo P-450/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Duocarmicinas/síntese química , Duocarmicinas/química , Humanos , Indóis/síntese química , Indóis/química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antineoplásicos Alquilantes/farmacologia , Duocarmicinas/farmacologia , Neoplasias/tratamento farmacológico , Animais , Anticorpos/imunologia , Antineoplásicos Alquilantes/química , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Duocarmicinas/administração & dosagem , Duocarmicinas/química , Humanos , Pró-Fármacos , Relação Estrutura-AtividadeRESUMO
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.