10-[Diethylaminopropylamino]-6-methyl-5H-pyrido[3',4':4,5] pyrrolo[2,3-g]
isoquinoline (BD-40) (NSC-327471D) is an aza-
ellipticine derivative with a promising antitumor activity (M. Marty, C. Jasmin, P. Pouillard, C. Gisselbrecht, G. Gouvenia, and H. Magdalainat, 17th Annual Meeting of the American Society of Clinical Oncology, C-108, 1981) and less toxicity than
ellipticine. We have compared the effects of
ellipticine, several of its analogues, and two aza-analogue
ellipticine derivatives (BD-40 and BR-1376) on cell cycle progression of BALB/c 3T3 mouse cells under different growth conditions. Both
drug series were found to stop cell growth and block cells in G2 phase in exponentially growing cultures and cultures released from a
thymidine double block. Long-term viability of these cells was completely suppressed after a short exposure to the drugs. In contrast, while
ellipticine and its derivatives caused identical effects in cells recovering from serum
starvation,
BD-40 and
BR-1376 did not block cells in G2 phase and did not prevent the completion of the first division round occurring after serum addition to quiescent cells. This transient refractory state was accompanied by a total conservation of long-term viability of these cells at least for the next 6 h following serum and
drug addition. This lack of effect was not related to an impaired
drug uptake by cells recovering from serum
starvation or by a dramatic change in
drug distribution inside the cells. These results indicate that the
nitrogen substitution in the
ellipticine heterocycle is an important if not unique feature for the particular effect of the aza-analogues of
ellipticine. Furthermore, they suggest that, in contrast to
ellipticine derivatives, these compounds require an activation step before exhibiting cytotoxicity.