Intercalative pyrimido[4',5':4,5]thieno(2,3-b)quinolines induce apoptosis in leukemic cells: a comparative study of methoxy and morpholino substitution

Shahabuddin, MS and Nambiar, Mridula and Advirao, Gopal M and Raghavan, Sathees C (2011) Intercalative pyrimido[4',5':4,5]thieno(2,3-b)quinolines induce apoptosis in leukemic cells: a comparative study of methoxy and morpholino substitution. In: Investigational New Drugs, 29 (5). pp. 873-882.

PDF Intercalative_pyrimido.pdf - Published Version Restricted to Registered users only Download (1MB) | Request a copy

Abstract

DNA intercalating molecules are promising anticancer agents. Polycyclic aromatic molecules such as ellipticine intercalate into double-stranded DNA and affect major physiological functions. In the present study, we have characterized two molecules with the same chemical backbone but different side chains, namely 8-methoxy pyrimido[4',5':4,5]thieno (2,3-b)quinoline-4(3H)-one (MPTQ) and 4-morpholino pyrimido[4',5':4,5]thieno(2,3-b)quinoline (morpho-PTQ) at the 8th and 4th position, respectively. Although both MPTQ and morpho-PTQ show similar biophysical properties with high DNA affinity, here we show that they differ in their biological activities. We find that MPTQ is many fold more potent than morpho-PTQ and is cytotoxic against different leukemic cell lines. IC(50) value of methoxy PTQ was estimated between 2-15 A mu M among the leukemic cells studied, while it was more than 200 A mu M when morpho-PTQ was used. Cell cycle analysis shows an increase in sub-G1 phase, without any particular cell cycle arrest. Annexin V staining in conjunction with comet assay and DNA fragmentation suggest that MPTQ induces cytotoxicity by activating apoptosis. Thus the observed low IC(50) value of MPTQ makes it a promising cancer chemotherapeutic agent.

Item Type:	Journal Article
Publication:	Investigational New Drugs
Publisher:	Springer
Additional Information:	Copyright of this article belongs to Springer.
Keywords:	Chemotherapy;Double-strand breaks;Cytotoxicity;DNA damage; Anticancer drug
Department/Centre:	Division of Biological Sciences > Biochemistry
Date Deposited:	16 Sep 2011 07:04
Last Modified:	16 Sep 2011 07:04
URI:	http://eprints.iisc.ac.in/id/eprint/40431

Actions (login required)

View Item