title: Intercalative pyrimido[4',5':4,5]thieno(2,3-b)quinolines induce apoptosis in leukemic cells: a comparative study of methoxy and morpholino substitution.
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 µM among the leukemic cells studied, while it was more than 200 µM 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.
authors.affiliation: Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.
authors.forename: M S
authors.initials: MS
authors.lastname: Shahabuddin
authors.forename: Mridula
authors.initials: M
authors.lastname: Nambiar
authors.forename: Gopal M
authors.initials: GM
authors.lastname: Advirao
authors.forename: Sathees C
authors.initials: SC
authors.lastname: Raghavan
mesh_terms: D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology*; D007938:Leukemia / Q000378:metabolism / Q000473:pathology*; D018613:Microscopy, Confocal; D060172:Morpholinos / Q000737:chemistry / Q000494:pharmacology*; D010718:Phosphatidylserines / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C488380:8-methoxypyrimido(4(1),5(1)-4,5)thieno(2,3-b)quinoline-4(3H)-one; D017304:Annexin A5; D007364:Intercalating Agents; D060172:Morpholinos; D010718:Phosphatidylserines; D011804:Quinolines; D013876:Thiophenes