Synthesis and biological evaluation of novel 3′-difluorovinyl taxoids

Abstract

A series of 3′-difluorovinyl taxoids with C10 modifications, as well as those with C2 and C10 modifications, were strategically designed to block the metabolism by cytochrome P-450 3A4 enzyme and synthesized. These novel difluorovinyl taxoids were evaluated for their cytotoxicity against drug-sensitive human breast (MCF7), multidrug-resistant (MDR) human ovarian (NCI/ADR), human colon (HT-29) and human pancreatic (PANC-1) cancer cell lines. 3′-Difluorovinyl taxoids exhibit several to 16 times better activity against MCF7, HT-29 and PANC-1 cell lines and up to three orders of magnitude higher potency against NCI/ADR cell line as compared to paclitaxel. Structure-activity relationship study shows the critical importance of the C2 modifications on the activity against MDR cancer cell line, while the C10 modifications have a rather minor effect on the potency with some exceptions. The effect of the C2 modifications on potency against MCF7 cell line increases in the following order: H < F < Cl <N3. Among the twenty five 3′-difluorovinyl taxoids evaluated, eight taxoids exhibited less than 100 pM IC50 values against MCF7 cell line. Difluorovinyl taxoids induced GTP-independent tubulin polymerization much faster than paclitaxel. Then, the resulting microtubules were stable to Ca2+-induced depolymerization, indicating strong stabilization of microtubules. Molecular modeling study indicated that a difluorovinyl taxoid binds to β-tubulin in a manner that is consistent with the REDOR-Taxol structure. The difluorovinyl group appears to mimic the isobutenyl group to some extent, but with very different electronic property, which may account for the unique activities of difluorovinyl taxoids.

Quest for Efficacious Next-Generation Taxoid Anticancer Agents and Their Tumor-Targeted Delivery

“…39 There was morphological similarity between those microtubules generated by the action of difluorovinyltaxoids and those by 21 and 1 , but the formation of thinner, shorter, and straight microtubules appears to be unique to difluorovinyltaxoids. 39 …”

“…39 A series of novel 3′-difluorovinyltaxoids were synthesized through the Ojima–Holton coupling of enantiopure (3 R ,4 R )-4-difluorovinyl-β-lactam with various baccatins with modifications at the 10 and/or 2 positions. 39 …”

Drug discovery targeting cell division proteins, microtubules and FtsZ

“…11 As Figure 4 shows, these three difluorovinyl taxoids induced GTP-independent tubulin polymerization much faster than paclitaxel. Thus, the turbidity of the tubulin solution treated with difluorovinyl taxoids reaches a plateau quickly and does not change with time.…”

“…32 In addition, we have investigated fluorine-containing second-generation taxoids, bearing CF 3 , CF 2 H and 2,2-difluorovinyl groups at the C3’ position of the N-t -Boc-isoserine moiety at the C13 position. 9–11, 33–38 Furthermore, we performed the SAR study on novel C-seco analogs of the second-generation taxoids for their activities against paclitaxel-resistant cancer cell lines overexpressing the Class III β-tubulin. 39 …”

“…2–4 We have been developing new-generation taxoids, which possess much higher potency than the first-generation taxanes, i.e., paclitaxel and docetaxel, particularly against drug-resistant cancer cell lines and tumor xenografts, wherein the drug resistance is caused by MDR, point mutation and β-tubulin subtypes (Figure 1). 5–11 These new-generation taxoids interact with microtubules in a manner different from that of paclitaxel and docetaxel.…”