Development of pyrrolo[2,1-c][1,4]benzodiazepine beta-galactoside prodrugs for selective therapy of cancer by ADEPT and PMT.
The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a class of well-studied DNA-interactive agents with a potential for use in the treatment of cancer. The clinical utility of these molecules is limited because of the lack of selectivity for tumor tissues, high reactivity of the pharmacophoric imine functionality, low water solubility, and stability. To address the shortcomings, especially the lack of selectivity, associated with the molecules, two new beta-galactoside prodrugs of PBDs have been synthesized and evaluated for their potential use in selective therapy of solid tumors by ADEPT and PMT protocols. The preliminary studies reveal the prodrugs to be much less toxic compared to the parent moieties. These prodrugs are activated by E. coli beta-galactosidase (EC 3.2.1.23) to form the active cytotoxic moiety signifying their utility in ADEPT of cancer. One of the significant outcomes of the present study is the toxification of the prodrug 1 a by the endogenous beta-galactosidase of human liver cancer cells (Hep G2) to form the cytotoxic moiety, enabling selective therapy of hepatocellular carcinoma. Another important property of these molecules is their enhanced water solubility and stability, which are essential for a molecule to be an effective drug.
Kamal
Ahmed
A
Department of Chemical Biology, Indian Institute of Chemical Technology, Hyderabad 500 007, India. ahmedkamal@iict.res.in
Tekumalla
Venkatesh
V
Krishnan
Anita
A
Pal-Bhadra
Manika
M
Bhadra
Utpal
U
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004355:Drug Stability; D005697:Galactosides / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D009369:Neoplasms / Q000628:therapy*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility
D000970:Antineoplastic Agents; D005697:Galactosides; D011355:Prodrugs; C007816:beta-galactoside; D001569:Benzodiazepines