SAR study of novel taxoids for macrophage activation and MDR-reversal activity

A series of paclitaxel analogs modified at position C-10, C-2 or C-7 have been prepared by means of the β-Lactam Synthon Method. These synthetic taxoids, together with two nor-seco analogs, were evaluated at the Jichi Medical School in Japan for their potency to induce NO and TNF-α production by peritoneal murine macrophages (M&phis;) from LPS-responsive C3H/HeN and LPS-hyporesponsive C3H/HeJ strains and by human blood cells, and for their ability to inhibit the growth of M&phis;-like cell lines J774.1 and J7.DEF3. In this structure-activity relationship study, we found that: (i) the nature of the substituents at C-10, C-2 and C-7 positions have a distinctive effect on the induction of TNF and NO production by M&phis;; (ii) a distinctive effect of the length of the substituent at the C-10 position is observed for analogs bearing an alkyl moiety at this position; (iii) analog SB-T-00321 is the most active taxoid so far in macrophage activation study and represents the first example of a structural correlation between a taxoid and LPS; (iv) an aromatic moiety at the C-2 position is required for the activity, while only hydroxyl or acetyl substituents seem to be tolerated by the C-7 position; (v) the natural stereochemistry of paclitaxel on the C-13 side chain of the taxoids is an absolute requirement for the activity; (vi) none of the taxoids tested stimulated TNF/NO production by C3H/HeJ M&phis;, with the exception of SB-T-02041, bearing a 3,3-dimethylpentanoyl group at the C-2 position; (vii) none of the taxoids tested stimulated TNF production by human blood cells; (viii) there is no correlation between the TNF/NO inducibility in C3H/HeN M&phis; and growth inhibition activity against M&phis;-like cells.;Various taxane analogs modified either at the C-7 or the C-10 position, derived from 10-deacetylbaccatin III, 14β-hydroxy-10-deacetylbaccatin III 1,14-carbonate or 13-oxo-10-deacetyl baccatin III, were synthesized and evaluated for their ability to reverse MDR in resistant breast cancer cell line MDA-435/LCC6-MDR1. This detailed SAR study on the benzophenone moiety, previously found to confer a remarkable high MDR-reversal activity to these TRAs, led to the following conclusions: (i) TRAs derived from 13-acetyl-14OH-baccatin 1,14-carbonate are slightly more active than the correspondent 13-acetylbaccatin III derivatives; (ii) the position of the side chain on the baccatin core plays an extremely important role; (iii) oxidation of the C-13 position leads to much less active TRAs; (iv) the carbonyl group between the two aromatic rings of the benzophenone moiety is essential for the activity, but may be replaced by certain heteroatom containing moieties; (v) saturation and lengthening of the side chain, as well as shortening to a single carbon, are detrimental for the activity; (vi) in general a rigid, conjugation-stabilized and planar aromatic side chain seems to be absolutely required for an efficient MDR-reversal activity.