Design and Synthesis of Coumarin Derivatives as Novel PI3K Inhibitors (original) (raw)
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European journal of medicinal chemistry, 2017
A small library of coumarins, carrying butynyl-amino chains, was synthesized continuing our studies in the field of MDR reverting ageEnts and in order to obtain multipotent agents to combat malignancies. In particular, the reported anticancer and chemopreventive natural product 7-isopentenyloxycoumarin was linked to different terminal amines, selected on the basis of our previously reported results. The anticancer behaviour and the MDR reverting ability of the new compounds were evaluated on human colon cancer cells, particularly prone to develop the MDR phenotype. Some of the new derivatives showed promising effects, directly acting as cytotoxic compounds and/or counteracting MDR phenomenon. Compound 1e emerged as the most interesting of this series, showing a multipotent biological profile and suggesting that conjugation of an appropriate coumarin core with a properly selected butynyl-amino chain allows to obtain novel hybrid molecules endowed with improved in vitro antitumor acti...
Journal of Heterocyclic Chemistry, 2018
Various new substituted and fused coumarin analogues have been synthesized via different synthetic pathways. Among which are variable substituted coumarin derivatives bearing either biologically active side chains or rings at 5, 6, and 3 positions of the coumarin nucleus as indicated in compounds 10, 12, 13, 16-19, 21, 23-32, 38, and 42-45. In addition, different pyranocoumarin derivatives either substituted as in compounds 2, 3, and 6 or fused as compounds 33-36, pyranoxanthene analogues such as compounds 4 and 46, coumarinotriazolothiadiazine derivative 8, coumarinonaphthodiazocin analogue 39 and coumarinopyrazolone derivative 40 were synthesized. Thirty-eight of the synthesized compounds were subjected to in vitro anticancer screening against mammalian liver carcinoma HepG2 and breast carcinoma MCF7 cell lines using Cisplatin as a standard reference. The anticancer activity screening results revealed that, among the tested compounds, compounds 16, 40, and 43 bearing 4-chlorophenyl-2-aminopyridine-3carbonitrile attached to C 6 position, fused pyrazolone ring or attached to 4-chlorophenyl-2-oxodihydropyridine-3-carbonitrile at C 3 position of the coumarin nucleus, respectively, exhibited moderate to strong activity against both cell lines.
2011
Six classes of coumarin derivatives (i.e. 3-alkyl-4-methylcoumarins, pyranocoumarins, coumarin carboxamides, quaternary ammonium coumarins, 7-aminocoumarins, and 4-aminocoumarins) were synthesized and evaluated for inhibition of cell proliferation of colon adenocarcinoma (HT-29), breast carcinoma (MDA-MB-468 or MCF-7), and human ovarian adenocarcinoma (SK-OV-3) cells. C-3-Alkyl substituted analogs of 4-methylcoumarins and pyranocoumarins, 5 and 6, inhibited the cell proliferation of MDA-MB-468 and SK-OV-3 cells by 53-74%, while 3-decyl substituted pyranocoumarin 10 and triethyl substituted quaternary ammonium coumarin derivative 29 inhibited the cell proliferation of HT-29 and SK-OV-3 cells by 63-72% at a concentration of 50 µM. Among all the compounds studied, C-3 decyl substituted quaternary ammonium coumarin derivative 25 exhibited the highest Src kinase inhibition with an IC 50 value of 21.6 µM.
European Journal of Medicinal Chemistry, 2015
Coumarins are fused benzene and pyrone ring systems which prompt biological investigation to assess their potential therapeutic significance. It possesses immeasurable anticancer potential with minimum side effects depending on the substitutions on the basic nucleus. Coumarins have a tremendous ability to regulate diverse range of cellular pathways that can be explored for selective anticancer activity. This is the first standalone review that emphasis on the assorted retrosynthetic approaches, important targets for molecularly targeted cancer therapy and structure activity relationship studies that highlight the chemical groups responsible for evoking the anticancer potential of coumarin derivatives reported from 2011 to 2014.
Anticancer Properties and Clinical Trials of Coumarins: A Review
Free Radicals and Antioxidants
Cancer has evolved as one of the most common causes of mortality, worldwide. Though numerous chemotherapeutic treatments are available, their side effects such as cytotoxicity and drug resistance form a big problem during the cancer treatment. Recent studies of anticancer activities conducted on natural products isolated from plants, namely coumarin and related compounds, prove them to be a promising drug candidate in cancer treatments. Efforts made by the scientists to design and develop novel anti-cancer agents using coumarins as lead compounds and study their effectiveness using Structural Activity Relationship is worth appreciating. This review, therefore, focuses on the recent progress in the discovery of coumarin derivatives with potential antitumor activity. It also summarizes their structureactivity relationship, and mechanism of action studies.
Cytotoxic and Antitumor Activity of some Coumarin Derivatives
Natural Product Communications
Several natural and synthetic coumarins were assayed against different cancer cell lines. Four of them have shown cytotoxicity against a panel of three human solid tumor cell lines (HeLa, T-47D, and WiDr) and a clearly activity/hydrophobicity relationship. Compound 13 proved to be the most active product in all cell lines tested, with values of 8.0 (±0.38) μM against HeLa cells and also able to inhibit Taq DNA polymerase. This dual activity of 13 makes it a candidate to be considered as a “lead” compound in the search for novel antitumor drugs.
Design, synthesis and discovery potent of novel anticancer agents based on the coumarin scaffold
2015
Several effective anticancer therapeutic drugs containing coumarin nucleus targeting carbonic anhydrase enzyme. Thus, some coumarin derivatives 1-22 were prepared. The structures of these compounds established on the basis of IR, 1 HNMR, 13 CNMR and MS data. Moreover, the optimization geometries for compounds 1-22 were discussed using DFT theory with B3LYP\6-311G base set. The molecular docking simulations into the active site of COX-2 were performed, and showed that, some compounds (7,8, 11,13,19b and 20) suitable inhibitor against CAII, and can used as anti-cancer drugs. These compounds (7,8, 11,13,19b and 20) were evaluated against Ehrlich solid carcinoma (EAC) tumor model in Swiss albino mice on dose 50µg. The activity was assessed using survival time and average increase in body weight, which showed that, administration of derivatives (7,8, 11,13,19b and 20) were effective in reducing solid tumor mass EAC cells. In silico, The ADMET profiles showed that, these compounds are goo...
Recent developments of C-4 substituted coumarin derivatives as anticancer agents
European Journal of Medicinal Chemistry, 2016
Cancer is a prominent cause of death in global. Currently, the numbers of drugs that are in clinical practice are having a high prevalence of side effect and multidrug resistance. Researchers have made an attempt to expand a suitable anticancer drug that has no MDR and side effect. Coumarin scaffold became an attractive subject due to their broad spectrum of pharmacological activities. Coumarin derivatives extensively explored for anticancer activities as it possesses minimum side effect along with multi-drug reversal activity. Coumarin derivatives can act by various mechanisms on different tumor cell lines depending on substitution pattern of the core structure of coumarin. Substitution on coumarin nucleus leads to the search for more potent compounds. In this review, we have made an effort to give a synthetic strategy for the preparation of C-4 substituted coumarin derivatives as anticancer agents based on their mechanism of action and also discuss the SAR of the most active compound.
American Journal of Pharmacy And Health Research, 2018
Herein we report an exploratory study based on the cytotoxicity and antiproliferative activity of four previously synthesized coumarins derivatives (compounds 1a-d). The cytotoxic effect of the compounds was assessed on mononuclear cells, which were obtained from blood samples of healthy donors and measured by XTT method. The antiproliferative activity experiments were developed using HeLa, CaSKi and SiHa cervical cancer cell lines, and was evaluated by the MTT assay. In every single experiment, Cisplatin as internal control was employed. The cytotoxic assessment revealed that the four compounds did not significantly affect the viability on normal cells, whereas the antiproliferative activity on cancer cells was variable, according to the substituent located at position 3 of the coumarin core. It is worth mentioning that compound 1c, compared with the other products, presented a remarkable effect against CaSKi cell line, likewise 1d but in HeLa cells. These findings suggest that there is a relationship between biological activity and the alkoxycarbonyl chain since this is the only structural difference among the four tested compounds. The results lead to conclude that butyl group which is the substituent in compound 1d, was the key element in the antiproliferative effect presented by the molecule against SiHa, CaSKi and HeLa cell lines.