Medicinal Chemistry of Combretastatin A4:  Present and Future Directions

Tron, Gian Cesare; Pirali, Tracey; Sorba, Giovanni; Pagliai, Francesca; Busacca, Sara; Genazzani, Armando A.

doi:10.1021/jm0512903

Cited by 597 publications

(494 citation statements)

References 98 publications

(224 reference statements)

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“…The 3,4,5-trimethoxyphenyl (ring A) and the cisorientation of the bridge between the two aryl rings are fundamental for efficient binding to tubulin [16][17][18]. To retain the cis-olefin configuration of CA-4, five-membered heterocyclic bridges such as imidazole, pyrazoline, and triazole [6,7,19,20] et al have been introduced into CA-4 to replace the double bond.…”

Section: Introductionmentioning

confidence: 99%

4,5‐Diaryl‐3‐aminopyrazole Derivatives as Analogs of Combretastatin A‐4: Synthesis and Biological Evaluation

Liu¹,

Cui²,

Chen³

et al. 2011

Archiv der Pharmazie

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A series of cis-restricted 4,5-diaryl-3-aminopyrazole derivatives were synthesized and tested for their cytotoxic activity in vitro against five human cancer cell lines (K562, ECA-109, A549, SMMC-7721, and PC-3). Compounds 5a, 5b, 5d, and 6b showed potent cytotoxicity against all tested cell lines. Primary mechanism research on compound 5a indicated that it was a potent inhibitor of tubulin polymerization, arresting cell cycle in G(2)/M phase. The docking research showed the conformation of 5a overlaps well with CA-4 in the crystallized protein complex, suggesting the 4,5-diaryl-3-aminopyrazoles were good mimics of CA-4.

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Section: Introductionmentioning

confidence: 99%

4,5‐Diaryl‐3‐aminopyrazole Derivatives as Analogs of Combretastatin A‐4: Synthesis and Biological Evaluation

Liu¹,

Cui²,

Chen³

et al. 2011

Archiv der Pharmazie

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“…Spontaneous isomerization to the trans-double bond observed both in vitro and in vivo causes a dramatic decrease of biological activity. 10 To stabilize the active cis-conformation, several heteroaromatic rings, such as pyrazole, 11 imidazole, 11,12 thiazole, 11 isoxazole, 13,14 1,2,3-thiadiazole, 15 isomeric triazoles, 11,16,17 and tetrazole 11,[18][19][20] have been introduced as a nonisomerizable and metabolically stable isosteric equivalent of cis-double bond (Figure 1, III), resulting in highly active microtubule destabilizing antimitotic agents. Replacement of the double bond by triazolopyrimidine yielded diaryl-o-substituted-triazolopyrimidines (Figure 1, IV) with pronounced cytotoxicity against human cancer cells both in vitro and in mouse xenograft model.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and antimitotic properties of ortho-substituted polymethoxydiarylazolopyrimidines

Chernyshova¹,

Tsyganov²,

Khrustalev³

et al. 2017

Arkivoc

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Ortho-substituted polymethoxydiarylazolopyrimidines were synthesized using polymethoxysubstituted benzaldehydes and acetophenones as starting material. X-ray crystallography data clearly confirmed that the subsequent cyclization of 3-amino-1,2,4-triazole with ketoaldehydes yielded polymethoxyphenylsubstituted 6,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidines as single isomers. All compounds were evaluated in vivo using phenotypic sea urchin embryo assay. 6-(4-Methoxyphenyl)-7-(3,4,5-trimethoxyphenyl)pyrazolo [1,5-a]pyrimidine showed antimitotic microtubule destabilizing activity. The importance of aryl rings substituents in diaryltriazolopyrimidines for their antiproliferative antitubulin effect has been suggested.

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“…CA-4 is a stilbenoid phenol isolated from the bark of the South African Bushwillow tree, Combretum caffrum. CA-4 and its prodrugs are antimicrotubule agents that bind to the colchicinebinding site (C-BS) [17] [18] and selectively target endothelial cells, thereby inducing the regression of unstable emerging tumor neovessels through interference with vascular endothelial-cadherin signaling [19]. CA-4P has recently received an orphan drug designation for the treatment of anaplastic thyroid cancer, medullary thyroid cancer and stage IV papillary or follicular thyroid cancer.…”

Section: Introductionmentioning

confidence: 99%

Novel Cytocidal Substituted Phenyl 4-(2-Oxoimidazolidin-1-yl) Benzenesulfonates and Benzenesulfonamides with Affinity to the Colchicine-Binding Site: Is the Phenyl 2-Imidazolidinone Moiety a New Haptophore for the Design of New Antimitotics?

Fortin¹,

Wei²,

Kotra³

et al. 2015

OJMC

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Phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) and phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamides (PIB-SAs) are new, potent combretastatin A-4 (CA-4) analogs designed on the basis of their common phenyl 2-imidazolidone moiety. This phenyl 2-imidazolidone group is a bioisosteric equivalent of the trimethoxyphenyl group also found in colchicine, podophyllotoxin and several other ligands of the colchicine-binding site (C-BS). In this study, we investigate the interactions involved in the binding of PIB-SO and PIB-SA into the C-BS. We describe three distinct pockets (I, II, and III) as key structural elements involved in the interactions between the * Corresponding author. S. Fortin et al. 10C-BS and PIB-SOs as well as PIB-SAs. We show that PIB-SOs and PIB-SAs adopt 4 and 3 distinct binding conformations, respectively, within the C-BS. The binding conformations I and IV are common to most PIB-SOs and PIB-SAs exhibiting high affinity for the C-BS and high cytocidal potency. In addition, binding conformation I is the main conformation adopted by PIB-SOs, PIB-SAs, T138067, ABT-751, colchicine and CA-4. We also observe that the sulfonate and the sulfonamide moieties of PIB-SOs and PIB-SAs are bioisosteric equivalents. Interestingly, we further find that a large portion of the phenyl 2-imidazolidinone moiety in these analogs does not bind to pocket I unlike the trimethoxyphenyl moiety found in several antimicrotubule agents such as colchicine, CA-4 and podophyllotoxin, suggesting that the phenyl 2-imidazolidinone group may represent a new haptophoric moiety useful for the design of new C-BS inhibitors mimicking the tropolone and the methoxylated phenolic moieties of colchicine and CA-4, respectively.

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Medicinal Chemistry of Combretastatin A4: Present and Future Directions

Cited by 597 publications

References 98 publications

4,5‐Diaryl‐3‐aminopyrazole Derivatives as Analogs of Combretastatin A‐4: Synthesis and Biological Evaluation

4,5‐Diaryl‐3‐aminopyrazole Derivatives as Analogs of Combretastatin A‐4: Synthesis and Biological Evaluation

Synthesis and antimitotic properties of ortho-substituted polymethoxydiarylazolopyrimidines

Novel Cytocidal Substituted Phenyl 4-(2-Oxoimidazolidin-1-yl) Benzenesulfonates and Benzenesulfonamides with Affinity to the Colchicine-Binding Site: Is the Phenyl 2-Imidazolidinone Moiety a New Haptophore for the Design of New Antimitotics?

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