Studies of Aromatic Nitrogen Mustard Conjugates as Potential Anticancer Agents

Kundu, Debsouri (2016) Studies of Aromatic Nitrogen Mustard Conjugates as Potential Anticancer Agents. Masters thesis, Indian Institute of Science Education and Research Kolkata.

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Abstract

We have presented here the synthesis, characterization, study of hydrolytic stability and potential anticancer activity of aromatic nitrogen mustard conjugates and metal complex. The complexation of the ligand (L1), N, N-bis(4-(bis(2-chloroethyl)amino)benzylidene)ethane-1,2-diamine, with PtII helped to reduce the rate of hydrolysis of L1. However, both L1 and Cis-[Pt(L1)Cl₂] (1) show similar toxicity in human breast adenocarcinoma (MCF-7) and hepatocellular carcinoma (HepG2) cell lines and is more efficient than cisplatin. In contrast L1 is ca. six fold less toxic to normal human foreskin fibroblasts (HFF42) and lung cancer cell line (A549) showing that the cytotoxicity has some kind of selectivity towards MCF-7 and HepG2. In addition, four compounds 2-(4-bis(2-chloroethyl)amino)benzylideneamino)-3-phenylpropan-1-ol (2), 2-(4-(bis(2-chloroethyl)amino)benzylideneamino)ethanol (3), 2-(4-bis(2-chloroethyl)aminobenzyl-amino)-3-phenylpropan-1-ol (4) and 2-(4-(bis(2-chloroethyl)amino)benzylamino)ethanol (5) having reduced amino acid conjugated through Schiff base linkage to an aromatic nitrogen mustard were also made to exploit possible higher consumption due to dearth of nutrients that the cancer cells face all the time as a result of higher metabolic demands. The Schiff bases and their reduced versions were designed to probe the effect of the lability of the linkage on the reactivity pattern. Compound 2 and 4 were probed for their cytotoxicity and it was found that the Schiff base compound 2 was ca. 10 fold more active in certain cancer cells (MCF-7: IC₅₀ = 11 μM; HepG2: IC50 = 13 μM) compared to normal human fibroblasts (HFF42: IC50 = 120 μM) and exhibited a better in vitro cytotoxicity pattern than the FDA approved nutrient based nitrogen mustard drug melphalan (IC50 > 200 μM).

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