Strategic incorporation of fluorine into taxoid anticancer agents for medicinal chemistry and chemical biology studies

Abstract

This account exemplifies our recent progress on the strategic incorporation of fluorine and organofluorine groups to taxoid anticancer agents and their tumor-targeted drug delivery systems (TTDDSs) for medicinal chemistry and chemical biology studies. Novel 3′-difluorovinyltaxoids were strategically designed to block the metabolism by cytochrome P-450, synthesized, and evaluated for their cytotoxicity against drug-sensitive and multidrug-resistant (MDR) human cancer cell lines. 3′-Difluorovinyltaxoids exhibited impressive activities against these cancer cell lines. More significantly, a representative 3′-difluorovinyltaxoid exhibited 230-33,000 times higher potency than conventional anticancer drugs against cancer stem cell-enriched HCT-116 cell line. Studies on the mechanism of action (MOA) of these fluorotaxoids were performed by tubulin polymerization assay, morphology analysis by electron microscopy (EM) and protein binding assays. Novel 19F NMR probes, BLT-F2 and BLT-S-F6, were designed by strategically incorporating fluorine, CF3 and CF3O groups into tumor-targeting drug conjugates. These 19F-probes were designed and synthesized to investigate the mechanism of linker cleavage and factors that influence their plasma and metabolic stability by real-time 19F NMR analysis. Time-resolved 19F NMR study on probe BLT-F2 revealed a stepwise mechanism for the release of a fluorotaxoid, which might not be detected by other analytical methods. Probe BLT-S-F6 were very useful to study the stability and reactivity of the drug delivery system in human blood plasma by 19F NMR. The clean analysis of the linker stability and reactivity of drug conjugates in blood plasma by HPLC and 1H NMR is very challenging, but the use of 19F NMR and suitable 19F probes can provide a practical solution to this problem.

19F NMR as a tool in chemical biology

“…(c) Chemical structure of BLT-F2 and BLT-S-F6. Figure 5a and Figure 5b were reproduced and adapted from [ 43 ], Figure 5c was reproduced from [ 44 ].…”

“…(c) Chemical structure of BLT-F2 and BLT-S-F6. Figure 5a and Figure 5b were reproduced and adapted from [43], Figure 5c was reproduced from [44]. could be directly employed to determine the IC 50 values in the basis of fluoride release, and the extent of GBBNF turnover investigated in the presence of cell extracts.…”

“…Ojima and collaborators have also employed functional ligandobserved NMR experiments to develop a range of novel 3′-difluorovinyltaxoids, such as BLT-F2 and BLT-S-F6 (Figure 5c), that are active against drug-sensitive and multidrug-resistant (MDR) human cancer cell lines [44]. Here, the incorporation of CF 3 and CF 3 O groups as NMR reporters into the tumour-targeting drug conjugates enabled the direct investigation of the mechanism of the pro-drug metabolic cleavage and the pharmacophore release by real-time 19 F NMR analysis.…”

Importance of Fluorine in Benzazole Compounds

“…18 F became a powerful tool used for detection of various cancer types [ 9 , 10 , 11 ]. Ojima has introduced fluorine into taxoid anticancer agents and studied their tumor-targeted drug delivery systems [ 12 ]. The 3′-difluorovinyltaxoids ( 5 ) possess ( Figure 3 ) an exceptional potency against human breast, ovarian, colon and pancreatic cancer cell lines three times higher in potency compared to that of paclitaxel against breast cancer cell lines MCF-7 (drug-sensitive) and a multidrug-resistant cell line NCI/ADR (drug-resistant) cancer cell lines respectively.…”

A new series of bicalutamide, enzalutamide and enobosarm derivatives carrying pentafluorosulfanyl (SF5) and pentafluoroethyl (C2F5) substituents: Improved antiproliferative agents against prostate cancer

“…[7][8][9] These factors combined have a substantial impact on molecular conformation of the drug, which may affect the binding affinity to the target protein. For these reasons, organofluorine structures have received and they are still receiving increasing attention in medicinal chemistry, [10][11][12][13][14][15] and currently, fluorine is found in about 20% of pharmaceuticals. 13 The trifluoromethyl, [16][17][18] difluoromethyl [19][20][21][22] and fluoromethyl groups 23 (in decreasing order) 24 are the most exploited fluorinated groups in medicinal chemistry.…”