Cytotoxic and antitumoral properties in a series of new, ring D modified, olivacine analogues

The present study describes the synthesis and pharmacological profiles of new olivacine related compounds, possessing a modified D ring. The impact of this modification has been evaluated with respect to the cytotoxic and in vivo antitumoral effects of these molecules and in comparison with parent S 16020-2 previously prepared and investigated in our laboratory. The D ring size and number of nitrogen atoms as well as the position of the aminoalkyl substituent have a profound impact on the cytotoxic and antitumoral profiles. Thus out of the prepared pyrazinocarbazole compounds, 2 is devoid of any substantial cytotoxic and antitumoral activities while the pyrimidocarbazole 3 has a similar profile compared to I (S 16020-2). L1210 and P388 in vivo antitumoral effects are lost for both imidazocarbazoles 4 and 5, but the former conserves an in vivo antitumoral effect on B 16 melanoma, this effect being the largest in the series. Structural similarities and differences amongst the studied compounds could be evidenced by calculation of global properties such as molecular electrostatic potentials (MEP maps) and partition coefficients (log P), thus adding information on the impact of chemical changes on these two parameters known to influence biological behavior. (C) 2004 Elsevier Ltd. All rights reserved.