Diversity through semisynthesis: the chemistry and biological activity of semisynthetic epothilone derivatives

Epothilones are myxobacterial natural products that inhibit human cancer cell growth through the stabilization of cellular microtubules (i.e., a "taxol-like” mechanism of action). They have proven to be highly productive lead structures for anticancer drug discovery, with at least seven epothilone-type agents having entered clinical trials in humans over the last several years. SAR studies on epothilones have included a large number of fully synthetic analogs and semisynthetic derivatives. Previous reviews on the chemistry and biology of epothilones have mostly focused on analogs that were obtained by de novo chemical synthesis. In contrast, the current review provides a comprehensive overview on the chemical transformations that have been investigated for the major epothilones A and B as starting materials, and it discusses the biological activity of the resulting products. Many semisynthetic epothilone derivatives have been found to exhibit potent effects on human cancer cell growth and several of these have been advanced to the stage of clinical development. This includes the epothilone B lactam ixabepilone (Ixempra®, which has been approved by the FDA for the treatment of advanced and metastatic breast cance

Diversity through semisynthesis: The chemistry and biological activity of semisynthetic epothilone derivatives

ISSN:1381-1991ISSN:1573-501

Synthesis, Microtubule-Binding Affinity, and Antiproliferative Activity of New Epothilone Analogs and of an EGFR-Targeted Epothilone-Peptide Conjugate.

A new simplified, epoxide-free epothilone analog was prepared incorporating an N-(2-hydroxyethyl)-benzimidazole side chain, which binds to microtubules with high affinity and inhibits cancer cell growth in vitro with nM potency. Building on this scaffold, a disulfide-linked conjugate with the purported EGFR-binding (EGFR, epidermal growth factor receptor) peptide GE11 was then prepared. The conjugate retained significant microtubule-binding affinity, in spite of the size of the peptide attached to the benzimidazole side chain. The antiproliferative activity of the conjugate was significantly lower than for the parent scaffold and, surprisingly, was independent of the EGFR expression status of cells. Our data indicate that the disulfide-based conjugation with the GE11 peptide is not a viable approach for effective tumor-targeting of highly potent epothilones and probably not for other cytotoxics

A high sensitivity low-power capacitive front-end for insulin injection pens

A low-power 14-bits first order incremental Analog-to-Digital Converter (ADC) is presented. Based on the charge balancing principle, this switched-capacitor (SC) circuit integrates the input signal multiple times to reach the targeted resolution, linearity and noise performances. The sensitivities to non-ideal effects usually plaguing analog CMOS SC circuits, such as amplifier finite open-loop gain, offset, noise, parasitic capacitances and charge-injection of the switches are discussed. Their impact on the conversion accuracy and speed are evaluated, and corresponding design constraints are deduced. The ADC is implemented in an Application Specific Integrated Circuit (ASIC) in an AMS0.35 mu m process and is aimed for a high accuracy capacitance sensing to monitor the insulin injection in pens for diabetics. A minimum resolution of 0.3 fF, proportional to a third of an injectable insulin unit is targeted. The ADC is made low-power, allowing thus to perform many measurements per day considering its implementation in a lithium battery powered injection pen system of six months' life cycle

The impact of cyclopropane configuration on the biological activity of cyclopropyl-epothilones

Two cis-12,13-cyclopropyl-epothilone B variants have been synthesized, differing only in the configuration of the stereocenters at C12 and C13. The syntheses were based on a common allylic alcohol intermediate that was converted into the corresponding diastereomeric hydroxymethyl-cyclopropanes by means of stereoselective Charette cyclopropanations. Macrocyclizations were accomplished through ring-closing metathesis (RCM). Substantial differences between the two compounds were found with regard to microtubule binding affinity, antiproliferative activity and their effects on the cellular microtubule network. While the analogue with the cyclopropane moiety oriented in a corresponding way to the epoxide configuration in natural epothilones was almost equipotent with epothilone A, the other was significantly less active. Based on these findings, natural epothilone-like activity of cis-fused 12,13-cyclopropyl-epothilone analogues is tightly linked to the natural orientation of the cyclopropane moiety.K.H.A. and F.Z.G. are indebted to the Swiss National Science Foundation (SNF) (project 205320-117594) and ETH Zürich for generous financial support. J.F.D. acknowledges financial support by the Ministerio de Economia of Spain and from the Comunidad de Madrid (projects BIO2013-42984-R and S2010/BMD-2457 BIPPED, respectively)

Synthesis, profiling, and bioactive conformation of trans-Cyclopropyl Epothilones

16 p.-6 fig.-2 tab.A series of new 3‐deoxy‐C(12),C(13)‐trans‐cyclopropyl‐epothilones have been prepared, bearing benzothiazole, quinoline, thiazol‐5‐ylvinyl, or isoxazol‐3‐ylvinyl side chains. For analogs with fused aromatic side chains, macrocyclic ring‐closure was based on ring‐closing olefin metathesis (RCM) of a precursor incorporating the fully elaborated heavy atom framework of the target structure (including the side chain moiety), while side chain attachment for the thiazole and isoxazole‐containing 16‐desmethyl analogs was performed only after establishment of the macrolactone core. Two approaches were elaborated for a macrocyclic aldehyde as the common precursor for the latter analogs that involved ring‐closure either by RCM or by macrolactonization. Benzothiazole‐ and quinoline‐based analogs were found to be highly potent antiproliferative agents; the two analogs with a thiazol‐5‐ylvinyl or an isoxazol‐3‐ylvinyl side chain likewise showed good antiproliferative activity but were significantly less potent than the parent epothilone A. Surprisingly, the desaturation of the C(10)−C(11) bond in these analogs was associated with a virtually complete loss in antiproliferative activity, which likely reflects a requirement for a ca. 60 ° C(10)−C(11) torsion angle in the tubulin‐bound conformation of 12,13‐trans‐epothilones.We are indebted to the Swiss National Science Foundation (F. G. Z.; project number 205320‐117594) and the ETH Zürich for generous financial support. This work was also supported by: Agencia Estatal de Investigación of Spain (grants CTQ2015‐64597‐C2‐1‐P to J. J. B., and CTQ2016‐76263P to A. C.) and Ministerio de Economia y Competitividad grant BFU2016‐75319‐R to J. F. D. P. (both AEI/FEDER, UE). The authors acknowledge networking contributions by the COST Action CM1407 ‘Challenging organic syntheses inspired by nature – from natural products chemistry to drug discovery’ and the COST action CM1470.Peer reviewe

Synthesis, profiling, and bioactive conformation of trans-Cyclopropyl Epothilones

16 p.-6 fig.-2 tab.A series of new 3‐deoxy‐C(12),C(13)‐trans‐cyclopropyl‐epothilones have been prepared, bearing benzothiazole, quinoline, thiazol‐5‐ylvinyl, or isoxazol‐3‐ylvinyl side chains. For analogs with fused aromatic side chains, macrocyclic ring‐closure was based on ring‐closing olefin metathesis (RCM) of a precursor incorporating the fully elaborated heavy atom framework of the target structure (including the side chain moiety), while side chain attachment for the thiazole and isoxazole‐containing 16‐desmethyl analogs was performed only after establishment of the macrolactone core. Two approaches were elaborated for a macrocyclic aldehyde as the common precursor for the latter analogs that involved ring‐closure either by RCM or by macrolactonization. Benzothiazole‐ and quinoline‐based analogs were found to be highly potent antiproliferative agents; the two analogs with a thiazol‐5‐ylvinyl or an isoxazol‐3‐ylvinyl side chain likewise showed good antiproliferative activity but were significantly less potent than the parent epothilone A. Surprisingly, the desaturation of the C(10)−C(11) bond in these analogs was associated with a virtually complete loss in antiproliferative activity, which likely reflects a requirement for a ca. 60 ° C(10)−C(11) torsion angle in the tubulin‐bound conformation of 12,13‐trans‐epothilones.We are indebted to the Swiss National Science Foundation (F. G. Z.; project number 205320‐117594) and the ETH Zürich for generous financial support. This work was also supported by: Agencia Estatal de Investigación of Spain (grants CTQ2015‐64597‐C2‐1‐P to J. J. B., and CTQ2016‐76263P to A. C.) and Ministerio de Economia y Competitividad grant BFU2016‐75319‐R to J. F. D. P. (both AEI/FEDER, UE). The authors acknowledge networking contributions by the COST Action CM1407 ‘Challenging organic syntheses inspired by nature – from natural products chemistry to drug discovery’ and the COST action CM1470.Peer reviewe