Synthesis, cytotoxicity, and QSAR study of new aza-cyclopenta[b]fluorene-1,9-dione derivatives

Abstract

Thirty novel derivatives of aza-cyclopenta[b]fluorene-1,9-dione were synthesized, and their cytotoxic activities were tested against HeLa, LS180, MCF-7, and Raji cancer cell lines by MTT assay. Two derivatives containing nitrofuryl moiety, including 10-(5-nitro-furan-2-yl)-2,3-dihydro-4-aza-cyclopenta[b]fluorene-1,9-dione (IC 50 range: 5.7-13.0μm) and 10-(5-Nitro-furan-2-yl)-2,3,4,10-tetrahydro-4-aza-cyclopenta[b]fluorene-1,9-dione (IC 50 range: 3.6-20.2μm), as well as 10-(2-Nitro-phenyl)-2,3,4,10-tetrahydro-4-aza-cyclopenta[b]fluorene-1,9-dione (IC 50 range: 3.1-27.1μm) with nitrophenyl moiety on C10 position, were the most effective compounds. Furthermore, the effect of physiochemical descriptors on the cytotoxicity was evaluated by quantitative structure-activity relationship analysis. The quantitative structure-activity relationship results showed that molecular dipole moment, molar refractivity, fragment-based parameters, and some topological indices were influential on the cytotoxic effect. Finally, the good correlation that was found among cytotoxic data obtained from different cell lines may be an implication of a common cytotoxic mechanism in these cell lines. These findings provide useful structural information for the rational design and synthesis of efficient chemotherapeutic agents for treatment for cancer. Thirty novel dihydro and tetrahydro analogous of aza-cyclopenta[b]fluorene-1,9-dione were synthesized and their cytotoxic activities were tested against HeLa, LS180, MCF-7 and Raji cancer cell lines by MTT assay. QSAR analysis determined that molecular dipole moment and fragment-based parameters were important for the activity of these derivatives in the HeLa, MCF-7 and Raji cell lines. © 2011 John Wiley & Sons A/S.