388566-86-7

Upstream product

• 951-82-6 3,4,5-trimethoxyphenyl acetic acid 
• 621-59-0 isovanillin 
• 39500-10-2 (E)-3-(3-acetoxy-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)acrylic acid 

Downstream Products

• 1322005-66-2 4β-((E)-3-(3-hydroxy-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)acrylamido)-4-deoxypodophyllotoxin 
• 853795-03-6 3-[3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-phenyl]-2-(3,4,5-trimethoxy-phenyl)-acrylic acid 
• 117048-62-1 combrestatin A₄ 
• 388566-87-8 methyl (E)-3-(3-hydroxy-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)prop-2-enoate 

Relevant academic research and scientific papers

Synthesis and antiproliferative activity of combretastatin derivatives with adamantane fragment

The work describes the synthesis of 2-adamantyl 7-[(2-{[(2E)-3-(3-hydroxy-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)prop-2-enoyl]amino}ethyl)amino]-7-oxoheptanoate and 7-[(2-{[(2E)-2-(3,4-dimethoxyphenyl)-3-(3-hydroxy-4-methoxyphenyl)prop-2-enoyl]amino}e

Synthesis and evaluation of antiproliferative microtubule-destabilising combretastatin A-4 piperazine conjugates

Microtubules are a validated clinical target for the treatment of many cancers. We describe the design, synthesis, biochemical evaluation, and molecular modelling studies of a series of analogues of the microtubule-destabilising agent, combretastatin A-4 (CA-4). Our series of 33 novel compounds contain the CA-4 core structure with modifications to the stilbene linking group, and are predominantly piperazine derivatives. Synthesis was achieved in a two-step process by firstly obtaining the acrylic acid via a Perkin reaction using microwave enhanced synthesis, followed by coupling using either DCC or Mukaiyama's reagent. All target compounds were screened for antiproliferative activity in MCF-7 breast cancer cells. Hydroxyl derivative (E)-3-(4-hydroxy-3-methoxyphenyl)-1-(4-phenylpiperazin-1-yl)-2-(3,4,5-trimethoxyphenyl) propenone (4m) displayed potent antiproliferative activity (IC50 = 190 nM). Two amino-containing derivatives, (E)-3-(3-amino-4-methoxyphenyl)-1-(4-phenylpiperazin-1-yl)-2-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (4q) and (E)-3-(3-amino-4-methoxyphenyl)-1-(4-(p-tolyl)piperazin-1-yl)-2-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (4x), were the most potent with IC50 values of 130 nM and 83 nM respectively. Representative compounds were shown to depolymerise tubulin, induce G2/M arrest and apoptosis in MCF-7 cells but not peripheral blood mononuclear cells, and induce cleavage of the DNA repair enzyme poly ADP ribose polymerase (PARP) in MCF-7 cells. Modelling studies predict that the compounds bind to tubulin within the colchicine-binding site. These compounds are a valuable addition to the library of CA-4 analogues and 4m, 4q and 4x will be developed further as novel, water-soluble molecules targeting microtubules.

Synthesis and in vitro cytotoxicity evaluation of β-carboline-combretastatin carboxamides as apoptosis inducing agents: DNA intercalation and topoisomerase-II inhibition

To explore a new set of cytotoxic agents, β-carboline-combretastatin carboxamide conjugates were designed, synthesized and evaluated for their in vitro cytotoxicity potential, DNA binding affinity and Topoisomerase-II (topo-II) inhibition activity. Among the designed hybrids, 10v and 10af have shown significant cytotoxic effect against A549 (lung cancer) cell line having IC50 value 1.01 μM and 1.17 μM respectively. Further, it was speculated that treatment with compound 10v may induce apoptosis among A549 cells, which was supported by Hoechst staining, DCFDA, Annexin V-FITC and morphological assays. Flow cytometric analysis revealed that the hybrid 10v arrests A549 cells in G2/M phase of cell cycle in a dose dependent manner. Amongst the active hybrids, most potent hybrid 10v was tested for DNA topo-II inhibition activity. Moreover, to further support the biological activity and to infer the mode of interaction between ligands and DNA, spectroscopy and molecular docking studies were carried out. The docking and spectroscopy results showed that the ligands exhibited an intercalative mode of binding with DNA and could efficiently bind to DNA and form topo-II ternary complex. Based on these experiments, the hybrids 10v and 10af were identified as proficient new scaffolds which need to be developed as hit molecules for therapeutic interest.

Synthesis and in Vitro Bioactivity of Polyunsaturated Fatty Acid Conjugates of Combretastatin A-4

Combretastatin A-4 (CA-4) (1) is a plant-derived anticancer agent binding to the tubulin colchicine site. Polyunsaturated fatty acids (PUFAs) are readily taken up by cancer cells and have been used to improve cell targeting. In the present study, four CA-4-PUFA conjugates were synthesized by coupling combretastatin A-4 (1) with several polyunsaturated fatty acids. The conjugates (2a-d) were characterized using spectroscopic methods. Their cytotoxicity was evaluated against human breast cancer cells (MCF-7), and the inhibition of tubulin polymerization was determined in vitro. All conjugates influenced tubulin polymerization, with the arachidonic acid conjugate (2c) displaying cytotoxicity similar in potency to the natural product CA-4 (1).

Design, synthesis, and biological evaluation of novel combretastatin A-4 thio derivatives as microtubule targeting agents

A series of novel combretastatin A-4 (CA-4) thio derivatives containing different molecular cores, namely α-phenylcinnamic acids (core 1), (Z)-stilbenes (core 2), 4,5-disubstituted oxazoles (core 3), and 4,5-disubstituted N-methylimidazoles (core 4), as cis-restricted analogues were designed and synthesized. They were selected with the use of a parallel virtual screening protocol including the generation of a virtual combinatorial library based on an elaborated synthesis protocol of CA-4 analogues. The selected compounds were evaluated for antiproliferative activity against a panel of six human cancer cell lines (A431, HeLa, MCF7, MDA-MB-231, A549 and SKOV) and two human non-cancer cell lines (HaCaT and CCD39Lu). Moreover, the effect of the test compounds on the inhibition of tubulin polymerization in vitro was estimated. In the series studied here, oxazole-bridged analogues exhibited the most potent antiproliferative activity. Compounds 23a, 23e, and 23i efficiently inhibited tubulin polymerization with IC50 values of 0.86, 1.05, and 0.85 μM, respectively. Thio derivative 23i, when compared to its oxygen analogue 23j, showed a 5-fold higher inhibitory impact on tubulin polymerization. Compounds 23e and 23i, which showed both best cytotoxic and antitubulin activity, were further studied in terms of their effect on cell cycle distribution and proapoptotic activity. Compound 23e induced a statistically significant block of the cell cycle at the G2/M phase in A431, HaCaT, HeLa, MCF-7, MDA-MB-231, and SKOV-3 cells to an extent comparable to that observed in CA-4. In HeLa and SKOV-3 cells incubated with 23i, a concentration-dependent block of the G2/M phase was observed. The proapoptotic effect of 23e and 23i in A431, HaCaT, MCF-7, MDA-MB-231, and SKOV-3 was demonstrated with ELISA assay and double staining with Annexin V-FITC/PI. The results indicated that compound 23e and 23i may serve as novel lead compounds in research on more effective anticancer agents.

Combretastatin amino sugar conjugate, its preparation process and its medical use

The invention relates to the field of medical chemistry, in particular to a Combretastatin (A-4, CA-4) amino sugar conjugate, and a preparation method and tumor blood vessel inhibition thereof. The Combretastatin amino sugar conjugate is good in water sol

A styrene acrylic compounds, compositions containing the same and application thereof (by machine translation)

This invention involves a kind of formula (I) compound benzene acrylic acid or of the structure, wherein the R 1, R 2, R 3, R 4 and R 5 each independently selected from hydrogen, hydroxy and methoxy group of, R 6 to have 3-6 carbon atoms straight chain alkyl. At the same time also relates to a pharmaceutical composition, which comprises the styrene acrylic compound, an organic carboxylic acid, pH regulator and optionally one or more pharmaceutically acceptable excipients, the pH value of said pharmaceutical composition for 6-8 ; wherein the styrene acrylic compound according to the weight of said pharmaceutical composition of 0.05-1.00%, of the organic carboxylic acid by weight of said pharmaceutical composition accounts for 0.01-0.50%. More relates to the compound and said said phenethyl acrylic acid compound in the preparation of a pharmaceutical composition for treating diabetes prevention and/or the application of the drug in the eye. (by machine translation)

Novel resveratrol-based substrates for human hepatic, renal, and intestinal UDP-glucuronosyltransferases

Trans-Resveratrol (tRes) has been shown to have powerful antioxidant, anti-inflammatory, anticarcinogenic, and antiaging properties; however, its use as a therapeutic agent is limited by its rapid metabolism into its conjugated forms by UDP-glucuronosyltransferases (UGTs). The aim of the current study was to test the hypothesis that the limited bioavailability of tRes can be improved by modifying its structure to create analogs which would be glucuronidated at a lower rate than tRes itself. In this work, three synthetic stilbenoids, (E)-3-(3-hydroxy-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)acrylic acid (NI-12a), (E)-2,4-dimethoxy-6-(4-methoxystyryl)benzaldehyde oxime (NI-ST-05), and (E)-4-(3,5-dimethoxystyryl)-2,6-dinitrophenol (DNR-1), have been designed based on the structure of tRes and synthesized in our laboratory. UGTs recognize and glucuronidate tRes at each of the 3 hydroxyl groups attached to its aromatic rings. Therefore, each of the above compounds was designed with the majority of the hydroxyl groups blocked by methylation and the addition of other novel functional groups as part of a drug optimization program. The activities of recombinant human UGTs from the 1A and 2B families were examined for their capacity to metabolize these compounds. Glucuronide formation was identified using HPLC and verified by β-glucuronidase hydrolysis and LC-MS/MS analysis. NI-12a was glucuronidated at both the -COOH and -OH functions, NI-ST-05 formed a novel N-O-glucuronide, and no product was observed for DNR-1. NI-12a is primarily metabolized by the hepatic and renal enzyme UGT1A9, whereas NI-ST-05 is primarily metabolized by an extrahepatic enzyme, UGT1A10, with apparent Km values of 240 and 6.2 μM, respectively. The involvement of hepatic and intestinal UGTs in the metabolism of both compounds was further confirmed using a panel of human liver and intestinal microsomes, and high individual variation in activity was demonstrated between donors. In summary, these studies clearly establish that modified, tRes-based stilbenoids may be preferable alternatives to tRes itself due to increased bioavailability via altered conjugation.

Synthesis and insect antifeedant activity of stilbene derivatives against Brontispa longissima Larvae

Continuing our search for natural product-based compounds for the control of B. longissima Larvae, 25 stilbene analogs were synthesized and evaluated for insect antifeedant activity against third-instar larvae of B. longissima for the first time. Among all the tested compounds, especially compounds 3a, 3c, and 6 showed pronounced antifeedant activities with AFC50 values of 0.218, 0.327, and 0.226 mg/mL, respectively. The different antifeedant activity ranges of these compounds indicated that variation of chemical structures in the stilbene skeleton markedly affected the activity profiles of this compound class, and some important SAR information has been revealed from it. In addition, to understand the structural requirements for antifeedant activities of the 25 synthesized stilbene analogs, a comparative molecular field analysis (CoMFA) model, which yielded the leave-one-out (LOO) cross-validated correlation coefficient (q 2) of 0.533 and a non-cross-validated correlation coefficient (r 2) of 0.929, was constructed. Together, these preliminary results may be useful in guiding further modification of stilbenes in the development of potential new antifeedants.

Design, synthesis and biological evaluation of novel aminosaccharide derivatives of combretastatin A-4

Combretastatin A-4 (CA-4), a natural vascular disrupting agent (VDA) with potent anti-cancer activity, is a promising lead compound in drug discovery. In view of the potential application of carbohydrates in medicinal chemistry, we designed and synthesized sixteen novel CA-4 aminosaccharide derivatives. In vitro anti-proliferative studies showed that compounds 7a and 7c significantly inhibited the growth of human umbilical vein endothelia cells (HUVEC) and other four cancer cell lines. Besides, preliminary structure-activity relationship (SAR) was also summarized. 2013 Bentham Science Publishers.