ABSTRACT
In the present work, we explore the possibility of introducing selectivity to existing chemotherapeutics via the design of non-pro-drug, bi-functional molecules comprising a microtubule-binding agent and a substrate for a disease-associated kinase. The design, synthesis, and in vitro biological evaluation of paclitaxel-thymidine and vinblastine-thymidine bi-functional conjugates are reported here. This work provides the first account of 'kinase-mediated trapping' of cancer therapeutics.
Subject(s)
Antineoplastic Agents/chemical synthesis , Drug Delivery Systems/methods , Neoplasm Proteins/metabolism , Neoplasms/pathology , Paclitaxel/administration & dosage , Protein Kinases/metabolism , Thymidine/administration & dosage , Vinblastine/administration & dosage , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Drug Design , Humans , Microtubules/metabolism , Neoplasms/drug therapy , Structure-Activity Relationship , Substrate SpecificityABSTRACT
The design, synthesis, and evaluation of two N-alkylmaleimide aldehydes have been achieved, which upon reductive alkylation with the C3'-amino group of doxorubicin (DOX) permits the preparation of DOX conjugates via Michael addition of thiol-containing vectors. This method enables the mild, facile, and high-throughput preparation of DOX conjugates that retain the basic C3'-nitrogen, a pre-requisite for topoisomerase II inhibition. Seven DOX-amino acid conjugates were prepared, each displaying similar inhibitory activity as the parent drug.
Subject(s)
Aldehydes/chemistry , Antineoplastic Agents/pharmacology , Chemistry, Pharmaceutical/methods , DNA Topoisomerases, Type II/metabolism , Doxorubicin/chemistry , Drug Design , Maleimides/chemistry , Aldehydes/metabolism , Anthracyclines/pharmacology , Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/pharmacology , DNA Topoisomerases, Type II/chemistry , Doxorubicin/pharmacology , Drug Evaluation, Preclinical , Drug Screening Assays, Antitumor , Humans , K562 Cells , Magnetic Resonance Spectroscopy , Models, Chemical , Nitrogen/chemistryABSTRACT
A general protocol for the synthesis of paclitaxel C-10 carbamates is described. The method entails MeI-mediated activation of 2'-O-TBS-7-O-TES-10-O-deacetyl-paclitaxel-10-O-carbonylimidazole prior to reaction with amines. This method is effective for the synthesis of paclitaxel C-10 derivatives, including bifunctional molecules.
