Total Synthesis and Biological Assessment of Benzimidazole‐Based Analogues of Epothilone A: Ambivalent Effects on Cancer Cell Growth Inhibition

Cachoux, Frédéric; Isarno, Thomas; Wartmann, Markus; Altmann, Karl‐Heinz

doi:10.1002/cbic.200500351

Cited by 34 publications

(36 citation statements)

References 31 publications

(18 reference statements)

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“…Based on the significant increase in cellular potency associated with a dimethylbenzimidazole side chain within the structural framework of the Epo B/D macrocycle, [73,104,159] this modification has been further investigated by Altmann and co-workers as a potential potency-enhancing element in combination with a variety of macrocycle modifications. [162][163][164] (In addition, it should also be noted that among analogues 93 and 94 (and additional related structures not shown herein), those incorporating a benzimidazole moiety exhibit the most favorable solubility properties in aqueous medium.) These studies revealed that the potency-enhancing effect of the dimethylbenzimidazole moiety is rather general in nature and extends to the corresponding analogues of Epo A and C, [162] of 3-deoxyEpo B (105), and also of trans-Epo A (106) and its 3-deoxy derivative (107).…”

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confidence: 73%

“…[162][163][164] (In addition, it should also be noted that among analogues 93 and 94 (and additional related structures not shown herein), those incorporating a benzimidazole moiety exhibit the most favorable solubility properties in aqueous medium.) These studies revealed that the potency-enhancing effect of the dimethylbenzimidazole moiety is rather general in nature and extends to the corresponding analogues of Epo A and C, [162] of 3-deoxyEpo B (105), and also of trans-Epo A (106) and its 3-deoxy derivative (107). [149] For example, compound 106 is essentially equipotent to Epo B (which is the most potent natural epothilone) against drug-sensitive human cancer cell lines (IC 50 values against the human cervix carcinoma cell line KB-31 are 0.25 nm and 0.29 nm for 106 and Epo B, respectively).…”

Section: Side Chain Modificationsmentioning

confidence: 94%

“…[149] Similar effects on the activity against multidrug-resistant KB-8511 cells have also been observed for other types of (structurally unrelated) epothilone analogues with increased polarity over the corresponding parent compound (decreased Clog P). [149,162] Based on this observation, Altmann and co-workers attempted to overcome the P-gp susceptibility of benzimidazole-derived epothilone analogues through replacement of the epoxide oxygen atom by a more lipophilic methylene group, thus leading to side-chain-modified cyclopropane derivatives 108 and 109. [163] The synthesis of 109 is summarized in Scheme 13 and includes the highly selective directed cyclopropanation of (15R!)…”

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confidence: 99%

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The Chemistry and Biology of Epothilones—The Wheel Keeps Turning

et al. 2007

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Epothilones have captured the attention of chemists, biologists, and drug researchers ever since they were found to inhibit human cancer cell growth through a “taxol‐like” mechanism over ten years ago. Today, at least seven epothilone‐derived agents have entered clinical trials. However, additional new and exciting analogues have emerged in recent years, suggesting that the potential of these natural products to serve as leads for new anticancer drugs is far from exhausted.

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confidence: 73%

Section: Side Chain Modificationsmentioning

confidence: 94%

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confidence: 99%

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The Chemistry and Biology of Epothilones—The Wheel Keeps Turning

et al. 2007

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“…These results show that 6 and 7 (binuclear silver complexes) are the most sensitive against both bacteria. These binuclear Ag(I)-NHC complexes (6 and 7) have relatively better anti-bacterial potential compared with their mononuclear counterparts (8)(9)(10), considering the fact that the number of Ag atoms in complexes 6 and 7 is twice that of complexes 8-10. This further underscores the existing literature that the number of silver centres within a complex molecule determines its biological activities.…”

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confidence: 98%

Benzimidazole‐based silver(I)–N‐heterocyclic carbene complexes as anti‐bacterials: synthesis, crystal structures and nucleic acids interaction studies

Asekunowo

Haque

Razali

et al. 2014

Applied Organom Chemis

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A series of new benzimidazolium salts as N-heterocyclic carbene (NHC) precursors has been synthesized. Reactions of these salts with Ag 2 O with varying metal-to-salt ratio facilitate the formation of a series of new binuclear and mononuclear Ag(I)-NHC complexes. All compounds were characterized using physicochemical and spectroscopic techniques. Single-crystal X-ray diffraction study reveals a binuclear structure for one of the complexes and a mononuclear one for two others. These complexes exist as cationic Ag(I)-NHC complexes with the chelation of carbene carbons to the silver centre in an almost linear manner. The compounds were screened for their anti-bacterial activities against Staphylococcus aureus (ATCC 12600) as a Gram-positive bacterium and Escherichia coli (ATCC 25922) as a Gram-negative bacterium. The results show that both bacteria appear markedly inhibited. Furthermore, the results suggest the possibility of steric variation as a modulation of the anti-bacterial activities. The nuclease activities of the compounds were assessed using gel electrophoresis and the results indicate that these complexes can cleave or degrade DNA and RNA via a non-oxidative mechanism.

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“…3 The [1,4] benzodiazepine framework is nowadays linked with antitumoral activity, in such sense pyrrolo [1,4]benzodiazepine B, 4,5 On the other hand, the benzimidazole unit is the key building block for a variety of derivatives that are known to play crucial roles in the functions of a number of anticancer, antimicrobial and antiviral compounds among others. [8][9][10][11][12][13] However, to the best of our knowledge, there are just a few works reporting the synthesis of benzimidazole rings fused to a [1,4]benzodiazepine framework. 14, 15 Skalitzky and co-workers described the synthesis of 5,6-dihydroimidazo[4,5,1-jk] [1,4] benzodiazepin-7(4H)-one derivatives A ( Figure 1) with a potent cytotoxic activity.…”

Section: Introductionmentioning

confidence: 99%