Synthesis and Evaluation of 4/5-Hydroxy-2,3-diaryl(substituted)-cyclopent-2-en-1-ones as cis -Restricted Analogues of Combretastatin A-4 as Novel Anticancer Agents (original) (raw)
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Bioorganic & Medicinal Chemistry Letters, 2002
A series of 2-(3,4,5-trimethoxyphenyl)-3-arylcyclopent-2-ene-1-ones (8a–8e) and their related analogues, including pentenone 9a, pentenol 10a, pentene 12a, and furane 15, were synthesized and evaluated for cytotoxicity against murine and human tumor cell lines. Compounds 8a–c, 8e and 9a showed strong cytotoxicity with IC50 values in the range of 8–34 ng/mL. Compound 8e exhibited significant anti-tumor activity in BDF1 mice bearing Lewis lung carcinoma cells with an inhibition ratio of 59%.Five compounds 8a–8e and their related analogues were synthesized and evaluated for cytotoxicity and anti-tumor activity. These compounds showed strong cytotoxicity with IC50 values in the range of 8–34 ng/mL. Compound 8e exhibited significant anti-tumor activity in BDF1 mice bearing Lewis lung carcinoma cells with an inhibition ratio of 59%.
Bioorganic & Medicinal Chemistry Letters, 1998
A series of cis-restricted combretastatin analogues with 5-membered heterocycles were synthesized and their inhibitory activity against microtubule assembly and cytotoxic activity against the colon 26 adenocarcinoma cancer cell line were evaluated. Some of the heterocyclic analogues showed potent antitubulin activity and cytotoxicity. Compounds 16 and 35 showed marked tumor growth suppression in the colon 26 murine tumor model.
Medicinal Chemistry, 2023
Diphenyl ether derivatives inhibit mycobacterial cell wall synthesis by inhibiting an enzyme, enoyl-acyl carrier protein reductase (InhA), which catalyses the last step in the fatty acid synthesis cycle of genus Mycobacterium. To select and validate a protein crystal structure of enoyl-acyl carrier protein reductase of Mycobacterium tuberculosis for designing inhibitors using molecular modelling, a cross-docking and correlation study was performed. A series of novel 1-(3-(3-hydroxy-4-phenoxyphenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl) ethan-1-ones were synthesized from this model and screened for their antitubercular activity against M. tuberculosis H37Rv. Compound PYN-8 showed good antitubercular activity on M. tuberculosis H37Rv (MIC = 4-7 µM) and Mycobacterium bovis (% inhibition at 10 µM = 95.91%). Cytotoxicity of all the synthesized derivatives was assessed using various cell lines, and they were found to be safe. Structure of PYN-8 was also confirmed by single-crystal X-ray diffraction. The molecular modelling studies also corroborated the biological activity of the compounds. Further, in silico findings revealed that all these tested compounds exhibited good ADME properties and drug likeness and thus may be considered as potential candidates for further drug development.
Acetyl analogs of combretastatin a-4: Synthesis and biological studies
Bioorganic & Medicinal …, 2011
The combretastatins have received significant attention because of their simple chemical structures, excellent antitumor efficacy and novel antivascular mechanisms of action. Herein, we report the synthesis of 20 novel acetyl analogs of CA-4 (1), synthesized from 3,4,5-trimethoxyphenylacetone that comprises the A ring of CA-4 with different aromatic aldehydes as the B ring. Molecular modeling studies indicate that these new compounds possess a 'twisted' conformation similar to CA-4. The new analogs effectively inhibit the growth of human and murine cancer cells. The most potent compounds 6k, 6s and 6t, have IC 50 values in the sub-lM range. Analog 6t has an IC 50 of 182 nM in MDA-MB-435 cells and has advantages over earlier analogs due to its enhanced water solubility (456 lM). This compound initiates microtubule depolymerization with an EC 50 value of 1.8 lM in A-10 cells. In a murine L1210 syngeneic tumor model 6t had antitumor activity and no apparent toxicity.
Design, synthesis and cytotoxic activities of naphthyl analogues of combretastatin A-4
Bioorganic & Medicinal Chemistry Letters, 2000
The 3,4,5-trimethoxyphenyl and 3-hydroxy-4-methoxyphenyl rings of combretastatin A-4 are deemed optimal for its activity as antimitotic agent. The replacement of either one by a naphthalene ring results in compounds with a potency comparable to that of the parent compound. These results show that the naphthalene ring is a good surrogate for the 3,4,5-trimethoxyphenyl or the 3-hydroxy-4-methoxyphenyl rings of combretastatin A-4
Bioorganic & Medicinal Chemistry, 2013
We here report the synthesis and biological evaluation of several combretastatin derivatives alkylated at the phenol hydroxyl group. Some of these derivatives contain an (E)-arylalkene fragment reminiscent of that present in some natural stilbenes like resveratrol. The cytotoxicities towards one human healthy kidney embryonic and two tumoral cell lines were determined. In addition, the ability of these compounds to inhibit the production of the vascular endothelial growth factor (VEGF) was measured. Finally, the expression of genes controlling the production of telomerase was measured. Some of the compounds were found to have an activity comparable or higher than that of combretastatin A4 in at least one of the aforementioned biological properties. The compounds with the (E)-arylalkene fragment were in general terms more active than the simple O-alkyl derivatives. However, no clear structure/activity correlations were perceived when comparing the observed compound activities across the three biological properties. This points out the existence of marked differences between the mechanisms responsible for their cytotoxicity. 2013 Elsevier Ltd. All rights reserved.
Synthesis and evaluation of double bond substituted combretastatins
European Journal of Medicinal Chemistry, 2005
A series of combretastatins substituted with epoxides, amides and small alkyl groups has been synthesised and evaluated for cytotoxicity and their ability to inhibit the assembly of tubulin. The methyl and ethyl substituted phenols 36, 44 have shown potent antimitotic effects whilst exhibiting reduced cytotoxicity.