1. Intercalative pyrimido[4',5':4,5]thieno(2,3-b)quinolines induce apoptosis in leukemic cells: a comparative study of methoxy and morpholino substitution
- Author
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Mridula Nambiar, M. S. Shahabuddin, Sathees C. Raghavan, and Gopal M. Advirao
- Subjects
DNA Replication ,Cell cycle checkpoint ,Stereochemistry ,DNA damage ,Apoptosis ,DNA Fragmentation ,Phosphatidylserines ,Thiophenes ,Biochemistry ,Morpholinos ,chemistry.chemical_compound ,Cell Line, Tumor ,Humans ,Pharmacology (medical) ,Annexin A5 ,Cytotoxicity ,Cell Proliferation ,Pharmacology ,Leukemia ,Microscopy, Confocal ,Cell Death ,Chemistry ,Cell Membrane ,G1 Phase ,Intercalating Agents ,Comet assay ,Oncology ,Cell culture ,Quinolines ,DNA fragmentation ,Drug Screening Assays, Antitumor ,DNA - 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.
- Published
- 2011