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Gemcitabine‐( 5′‐phosphoramidate )‐[anti‐ IGF ‐1R]: molecular design, synthetic organic chemistry reactions, and antineoplastic cytotoxic potency in populations of pulmonary adenocarcinoma (A549)
Author(s) -
Coyne Cody P.,
Narayanan Lakshmi
Publication year - 2017
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12845
Subject(s) - gemcitabine , phosphoramidate , chemistry , cytotoxicity , combinatorial chemistry , carbodiimide , stereochemistry , organic chemistry , biochemistry , chemotherapy , in vitro , biology , genetics
One molecular‐based approach that increases potency and reduces dose‐limited sequela is the implementation of selective ‘targeted’ delivery strategies for conventional small molecular weight chemotherapeutic agents. Descriptions of the molecular design and organic chemistry reactions that are applicable for synthesis of covalent gemcitabine‐monophosphate immunochemotherapeutics have to date not been reported. The covalent immunopharmaceutical, gemcitabine‐( 5′‐phosphoramidate )‐[anti‐ IGF ‐1R] was synthesized by reacting gemcitabine with a carbodiimide reagent to form a gemcitabine carbodiimide phosphate ester intermediate which was subsequently reacted with imidazole to create amine‐reactive gemcitabine‐( 5′‐phosphorylimidazolide ) intermediate. Monoclonal anti‐ IGF ‐1R immunoglobulin was combined with gemcitabine‐( 5 ′‐ phosphorylimidazolide ) resulting in the synthetic formation of gemcitabine‐( 5′‐phosphoramidate )‐[anti‐ IGF ‐1R]. The gemcitabine molar incorporation index for gemcitabine‐( 5′‐phosphoramidate )‐[anti‐ IGF ‐R1] was 2.67:1. Cytotoxicity Analysis – dramatic increases in antineoplastic cytotoxicity were observed at and between the gemcitabine‐equivalent concentrations of 10 −9  M and 10 −7  M where lethal cancer cell death increased from 0.0% to a 93.1% maximum (100.% to 6.93% residual survival), respectively. Advantages of the organic chemistry reactions in the multistage synthesis scheme for gemcitabine‐( 5′‐phosphoramidate )‐[anti‐ IGF ‐1R] include their capacity to achieve high chemotherapeutic molar incorporation ratios; option of producing an amine‐reactive chemotherapeutic intermediate that can be preserved for future synthesis applications; and non‐dedicated organic chemistry reaction scheme that allows substitutions of either or both therapeutic moieties, and molecular delivery platforms.

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