STRUCTURAL SIGNIFICANCE OF THE BENZOYL GROUP AT THE C-3'-N POSITION OF PACLITAXEL FOR NITRIC-OXIDE AND TUMOR-NECROSIS-FACTOR PRODUCTION BY MURINE MACROPHAGES

The antitumor agent paclitaxel (Taxol) mimics the actions of lipopolys accharide (LPS) on murine macrophages (M phi). Recently, we have shown that the benzoyl group at the C-3' position of paclitaxel is the most important site to induce nitric oxide (NO) and tumor necrosis factor (TNF) production by C3H/HeNM phi (Biochem. Biophys. Res. Commun. 210, 678-686, 1996). In the present study, synthetic analogs of paclitaxel with replacement of the C-3'-N position were examined for their potenc ies to induce NO and TNF production by peritoneal M phi of LPS-respons ive C3H/HeN mice and LPS-hyporesponsive C3H/HeJ mice, by human blood c ells and human M phi. In this structure-activity relationship study, w e found that (i) the p-substitution of the benzoyl group definitely af fects the activity to activate C3H/HeN M phi, (ii) the analogs having a methyl or chloro group at the p-position exhibit stronger activity t han that of paclitaxel, (iii) there is good correlation between NO and TNF production by the M phi in response to compounds, (iv) the compou nds tested do not induce either NO or TNF production by C3H/HeJ M phi or TNF production by human cells, (v) a previous treatment of C3H/HeN M phi with the inactive compounds can hardly affect either paclitaxel- or LPS-induced TNF production by the M phi, (vi) paclitaxel and its a nalogs marginally affect LPS-induced TNF production by human blood cel ls, and (vii) there is no correlation between the NO/TNF inducibility to C3H/HeN M phi and growth inhibitory activity against M phi-like 577 4.1 and J7.DEF3 cells. (C) 1998 Academic Press.