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Development of Pyrrolo[2,1‐ c ][1,4]benzodiazepine β‐Galactoside Prodrugs for Selective Therapy of Cancer by ADEPT and PMT
Author(s) -
Kamal Ahmed,
Tekumalla Venkatesh,
Krishnan Anita,
PalBhadra Manika,
Bhadra Utpal
Publication year - 2008
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200700328
Subject(s) - prodrug , chemistry , adept , moiety , combinatorial chemistry , small molecule , pharmacology , stereochemistry , biochemistry , medicine
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 β‐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 β‐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 β‐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.