title: An improved synthesis of lysosomal activated mustard prodrug for tumor-specific activation and its cytotoxic evaluation.
abstract: Cyclophosphamide, an alkylating agent widely used as anticancer agent, biotransformed in vivo to unstable phosphoramidic mustard and acrolein, where the latter metabolite has been found responsible for hemorrhagic cystitis and renal toxicity. Being one of the most popular strategies to avoid these deleterious effects, prodrug design has been attempted, which can, in addition, enable selective drug targeting. Our efforts to design, synthesize and evaluate the enzymatically activated prodrug phosphorodiamidic mustard as potential candidate for selective chemotherapy in antibody-directed enzyme prodrug therapy or prodrug monotherapy strategies are described. We propose an improved synthesis of prodrug 14, consisting of a galactose moiety, a spacer and a cytotoxic drug and its cytotoxicity has been investigated. The prodrug 14 has been found to be nontoxic (in vitro) which could be a valuable candidate for further development.
authors.affiliation: Medicinal Chemistry Research Division, University College of Pharmaceutical Sciences, Kakatiya University, Warangal, India.
authors.forename: Raghuramreddy
authors.initials: R
authors.lastname: Adidala
authors.forename: Harikrishna
authors.initials: H
authors.lastname: Devalapally
authors.forename: Chandrasekhar
authors.initials: C
authors.lastname: Srivari
authors.forename: Krishna
authors.initials: K
authors.lastname: Devarakonda R
authors.forename: Raghuram Rao
authors.initials: RR
authors.lastname: Akkinepally
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002470:Cell Survival / Q000187:drug effects; D003520:Cyclophosphamide / Q000009:adverse effects / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000009:adverse effects; D015195:Drug Design; D004355:Drug Stability; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000378:metabolism; D005260:Female; D005697:Galactosides / Q000009:adverse effects / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008247:Lysosomes / Q000378:metabolism*; D061986:MCF-7 Cells; D010752:Phosphoramide Mustards / Q000009:adverse effects / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011355:Prodrugs / Q000009:adverse effects / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D001616:beta-Galactosidase / Q000737:chemistry / Q000378:metabolism
chemical_list: C577309:3,5-di(hydroxy)-2-((hydroxy)methyl)-6-(4-(((di(bis(2-chloroethyl)amino)phosphoryl)oxy)methyl)phenoxy)tetrahydro-2H-4-hydroxypyranose; D000911:Antibodies, Monoclonal; D018906:Antineoplastic Agents, Alkylating; D029968:Escherichia coli Proteins; D005697:Galactosides; D010752:Phosphoramide Mustards; D011355:Prodrugs; D003520:Cyclophosphamide; D001616:beta-Galactosidase