Biological properties of 8-methoxypyrimido[4(1),5(1):4,5]thieno(2,3-b)quinoline-4(3H)-one, a new class of DNA intercalating drugs.

BACKGROUND & OBJECTIVES: The compounds containing novel tetracyclic condensed quinoline ring system is of interest because of its close relationship with anticancer drug ellipticine. 8-Methoxypyrimido[4(1),5(1):4,5]thieno(2,3-b)quinoline-4(3H)-one (MPTQ) was investigated to study its effect on in vitro growth inhibition and clonogenic cell survival assay on three tumour cell lines, human promyelocytic leukemia HL-60, melanoma B16F10 and neuro 2a. A systematic study was carried out to evaluate its antitumour efficacy against B16 murine melanoma. Antiinflammatory and analgesic activities of MPTQ were also studied.

METHODS

The cytotoxicity of MPTQ on HL-60, B16F10 and neuro 2a cells was estimated by trypan blue exclusion test. The antitumour activity was evaluated using single dose, multiple/daily injections (days 3-6) or intermittent treatments over two weeks against s.c. implanted B16melanoma, both in terms of increased life span and tumour growth inhibition. Antiinflammatory activity was seen on carrageenan induced hind paw oedema. Counting the number of abdominal constrictions after the injection of acetic acid assessed the analgesic response.

RESULTS

MPTQ is cytotoxic to all the cell lines tested and ID50 being in the range of 0.08-1.0 microM. MPTQ was studied for anticancer activity in the clonogenic assay. Drug was applied over a wide dose range by 24 h exposure, yielding clear dose-response effects. In vivo antitumour efficacy against B16 melanoma showed evidence of major antitumour activity for MPTQ. Single and multiple i.p. doses of drug proved high level activity against the s.c. grafted B16melanoma, significantly increasing survival (P<0.001) and inhibiting tumour growth (T/C of 3.0%). A reduction (76.48%) in paw volume was noted in 40 mg/kg dose of which was comparable to antiinflammatory activity of 150 mg/kg i.p. of phenylbutazone. Analgesic activity was found to be of peripheral type as there was reduction of 74 per cent in writhing response by MPTQ in dose of 40 mg/kg in mice.

INTERPRETATION & CONCLUSION: The results suggested that the compounds containing pyrimidothienoquinoline system particularly 8-methoxy derivative might be potentially useful antitumour agent. We conclude that the correlation of physicochemical properties of the new series of pyrimidothienoquinolines with their pharmacological properties, might help in trying to understand the mechanism of pyrimidothienoquinolines series.