Molecular Design and Chemical Synthesis of a Highly Potent Epothilone

Abstract

De novo designed and synthesized methylthiopyrazole epothilone B boasts a stunning biological profile against tumor cells, with activity at sub‐nanomolar (IC50=0.06 nm) concentrations.

An efficient practical chemo-enzymatic protocol for the synthesis of pyrazoles in aqueous medium at ambient temperature

“…The formation of desired products ( Table 2, entries 1-12) was confirmed from IR, 1 HNMR, 13 CNMR spectra as well as by mass spectroscopy and in accordance with literature. The 1 HNMR of each product exhibited a singlet in the range ı = 5.98-6.19 ppm due to CH of the pyrazole ring.…”

“…Methylthiopyrazole epothilone B (Fig. 1, III) shows strong antitumor activity through the stabilisation of microtubules by binding with tubulin [13]. Due to unique biological activities of pyrazole derivatives in medicinal chemistry, the development of elegant and efficient ways enabiling facile access to this heterocycle is desirable.…”

Efficient synthesis of 1,3-diaryl-4-halo-1H-pyrazoles from 3-arylsydnones and 2-aryl-1,1-dihalo-1-alkenes

“…These dipolar compounds are readily prepared in two steps from N-functionalized amino acids, and are readily stored and handled. Methods have been disclosed for the [3 + 2] dipolar cycloaddition of sydnones with alkenyl silanes [18] and stannanes [18], alkenyl arenes [19], 1,3-dienes [20–21], α,β-unsaturated esters [19,22] and nitriles [23], phosphane oxides [24] or with alkynyl silanes [18], stannanes [18,25–26], arenes [27–28], esters [29–33], boronic esters [34–35]. However, the cycloaddition of sydnones with 1,1-dihaloalkenes is unknown, as is the direct formation of 4-halopyrazoles through the [3 + 2] dipolar cycloaddition of sydnones.…”

Total Synthesis and Selective Activity of a New Class of Conformationally Restrained Epothilones

“…[22] The extensive database on SAR for epothilone has led to the discovery of potent epothilones. [23,24] At least five analogues are currently in different stages of clinical development. [7] Most of the current potent epothilone analogues bear close structural resemblance to the parent compounds.…”