Antitumor activity of 4-amino and 8-methyl-4-(3diethylamino propylamino)pyrimido[4′, 5′:4,5]thieno (2,3-b) quinolines

The interaction of 4-aminopyrimido [4, 5':4,5] thieno (2,3-b) quinoline and 8-methyl-4-(3-diethylaminopropylamino) pyrimido [4', 5:4,5] thieno (2,3-b) quinoline with DNA was studied by UV-Vis and fluorescence spectrophotometry as well as by hydrodynamic methods. On binding to DNA, the absorption spectra underwent bathochromic and hypochromic shifts and the fluorescence was quenched. These compounds are able to bind to DNA with an affinity of about 10(6) M-1 for calf thymus DNA at ionic strength 0.01 M and their intercalating characteristic (lengthening of the DNA) depends upon the length of the chain. Binding to the GC-rich DNA of Micrococcus lysodeikticus was stronger than the binding to calf thymus DNA at ionic strength 0.01 M. The cytotoxicities of these compounds on leukemia HL-60, melanoma B16F10 and neuro 2a cells are quite similar and inhibition (IC50) is in the range of 0.992-3.968 muM. The anticancer efficacy against B16 melanoma, has provided evidence of major antitumor activity for 8-methyl-4(3diethylaminopropylamino) pyrimido [4', 5:4,5] thieno(2,3-b)quinoline. Single or multiple intraperitonial (i.p) doses of drug proved high level activity against the subcutaneous (s.c) grafted B16 melanoma, significantly increasing survival (P < 0.001) and inhibiting tumor growth (T/C of 4%). This study offers a new intercalation functional group to DNA - targeted drug design. (C) 2003 Elsevier B.V. All rights reserved.