Search

A potential microtubule destabilising series of new indolizine derivatives was synthesised and tested for their anticancer activity against a panel of 60 human cancer cell lines. Compounds 11a, 11b, 15a, and 15j showed a broad spectrum of growth inhibitory activity against cancer cell lines representing leukaemia, melanoma and cancer of lung, colon, central nervous system, ovary, kidney, breast, and prostate. Among them, compound 11a was distinguishable by its excellent cytostatic activity, showing GI50 values in the range of 10–100 nM on 43 cell lines. The less potent compounds 15a and 15j in terms of GI50 values showed a high cytotoxic effect against tested colon cancer, CNS cancer, renal cancer and melanoma cell lines and only on few cell lines from other types of cancer. In vitro assaying revealed tubulin polymerisation inhibition by all active compounds. Molecular docking showed good complementarity of active compounds with the colchicine binding site of tubulin., Graphical Abstract

We report the synthesis and biochemical evaluation of compounds that are designed as hybrids of the microtubule targeting benzophenone phenstatin and the aromatase inhibitor letrozole. A preliminary screening in estrogen receptor (ER)-positive MCF-7 breast cancer cells identified 5-((2H-1,2,3-triazol-1-yl)(3,4,5-trimethoxyphenyl)methyl)-2-methoxyphenol 24 as a potent antiproliferative compound with an IC50 value of 52 nM in MCF-7 breast cancer cells (ER+/PR+) and 74 nM in triple-negative MDA-MB-231 breast cancer cells. The compounds demonstrated significant G2/M phase cell cycle arrest and induction of apoptosis in the MCF-7 cell line, inhibited tubulin polymerisation, and were selective for cancer cells when evaluated in non-tumorigenic MCF-10A breast cells. The immunofluorescence staining of MCF-7 cells confirmed that the compounds targeted tubulin and induced multinucleation, which is a recognised sign of mitotic catastrophe. Computational docking studies of compounds 19e, 21l, and 24 in the colchicine binding site of tubulin indicated potential binding conformations for the compounds. Compounds 19e and 21l were also shown to selectively inhibit aromatase. These compounds are promising candidates for development as antiproliferative, aromatase inhibitory, and microtubule-disrupting agents for breast cancer.

In this study, (3,4-dimethoxyphenyl) (3,4,5-trimethoxyphenyl) methanone (7) being phenstatin derivation was synthesized using Eaton's reagent (CH3SO3H / P2O5). Novel compound (2-bromo-3,4,5-trimethoxyphenyl) (3,4-dimethoxyphenyl) methanone (10) and (2,6-dibromo-3,4,5-trimethoxyphenyl) (3,4-dimethoxyphenyl) methanone (11) were synthesized with the bromination of diarylmethanone 7 with ceric (IV) ammonium nitrate (CAN/LiBr). In order to determine the structures of the compounds synthesized, IR, HRMS, 1H and 13C NMR spectroscopic analysis were used. Geometrical parameters of the products were optimized with the density functional theory (DFT) B3LYP method using the 6-311G(d,p) basis set implemented Gaussian 09 and analyzed their structural parameters (bond lenghts, bond angles, dihedral angles).

Three series of fused pyrrolophenanthroline derivatives were designed as analogues of phenstatin and synthesized in two steps starting with 1,7-phenanthroline, 4,7-phenanthroline and 1,10-phenanthroline, respectively. Two (Compounds 8a and 11c) of the four compounds tested against a panel of sixty human cancer cell lines of the National Cancer Institute (NCI) exhibited significant growth inhibition activity on several cell lines. Compound 11c showed a broad spectrum in terms of antiproliferative efficacy with GI50 values in the range of 0.296 to 250 &mu, M. Molecular docking studies indicated that Compounds 8a and 11c are accommodated in the colchicine binding site of tubulin in two different ways.

Background: Phenstatin and their derivatives display remarkable antiproliferative activity toward a wide variety of preclinical tumor models. Structural simplicity and excellent stability of phenstatins offer a stimulating premise for developing various derivatives with profound antimitotic activity and excellent cytotoxicity. Objective: To do analysis of literature that phenstatins derivatives inhibit tubulin polymerization through their interaction at the colchicine binding site of microtubules and arrest the G2/M phase of the cell cycle. In addition, phenstatin derivatives are undergoing clinical evaluation as vascular targeting/disrupting agents and also exhibit direct antiangiogenic properties. Methods: An organised well designed and appropriately managed search of bibliographic databases for peer-reviewed research literature using a focused review question and inclusion/ exclusion criteria has been done for this article. Conclusion: In this review article, the synthesis and structure-activity relationships of phenstatin and a wide number of their reported analogues with modifications to ring A, ring B, and to the keto position are discussed in the perspective of medicinal chemistry with proper conclusion.

New phenstatin-fatty acid conjugates have been synthesized and tested against the KB-3-1, H460, MCF-7 and HEK293 cell lines, with an increase in anti-proliferative activity being observed at the micro-molar level paralleling an increase in un-saturation in the fatty acid component.

Buçalışmada, Eaton reaktifi (CH3SO3H/P2O5)kullanılarak fenstatin türevi olan (3,4-dimetoksifenil)(3,4,5-trimetoksifenil)metanon(7) sentezlendi. Diarilmetanon 7’nin seryum (IV) amonyum nitrat (CAN/LiBr)kullanılarak bromlanması ile (2-brom-3,4,5-trimetoksifenil)(3,4-dimetoksifenil)metanon(10) ve (2,6-dibrom-3,4,5-trimetoksifenil) (3,4-dimetoksifenil)metanon (11)sentezlendi. Sentezlenen bileşiklerin yapıları IR, HRMS, 1H ve 13C NMRspektroskopisi ile aydınlatıldı. Bileşiklerin geometrik parametreleri GAUSSIAN09W paket programı kullanılarak, yoğunluk fonksiyonel teorisi (DFT)B3LYP/6-311G(d,p) metodu ile optimize edildi ve yapısal parametreleri (bağaçıları, bağ uzunlukları ve dihedral açıları) incelendi., In this study,(3,4-dimethoxyphenyl) (3,4,5-trimethoxyphenyl) methanone (7) being phenstatinderivation was synthesized using Eaton'sreagent (CH3SO3H / P2O5). Novelcompound (2-bromo-3,4,5-trimethoxyphenyl) (3,4-dimethoxyphenyl) methanone (10)and (2,6-dibromo-3,4,5-trimethoxyphenyl) (3,4-dimethoxyphenyl) methanone (11)were synthesized with the bromination ofdiarylmethanone 7 with ceric (IV) ammonium nitrate (CAN/LiBr). In order to determine the structures of thecompounds synthesized, IR, HRMS, 1H and 13C NMRspectroscopic analysis were used. Geometricalparameters of the products were optimized with the density functional theory(DFT) B3LYP method using the 6-311G(d,p) basis set implemented Gaussian 09 andanalyzed their structural parameters (bond lenghts, bond angles, dihedralangles).

A new four-step approach for the synthesis of anticancer agentcombretastatin A-4 (CA-4) has been developed. The method includesthe Colvin rearrangement of the benzophenone derivative phenstatinto the key diarylalkyne followed by stereoselective semi-reductionto CA-4 in good overall yield.

A simple and convenient two-step synthesis of hydroxyphenstatin (2) is reported by condensing 3,4,5-trimethoxybenzoic acid with pyrogallol and subsequent selective methylation with dimethyl sulphate in presence of potassium carbonate.

The π-cationic arylation of methoxy substituted benzoic acids with reactive arenes [e.g. (II)] is developed to provide an optimized synthetic route to phenstatin (V).

6 Phenstatin or isophenstatin-containing esters of oleic, linoleic and stearic acid of type (VII) or (VIII) are prepared by a reaction sequence as outlined for (VII).

International audience; With the aim of investigating the influence of fluorine, in particular on the A-ring, a new series of fluoro analogues (7a-l) of phenstatin (3) was synthesized and tested for interactions with tubulin polymerization and evaluated for cytotoxicity on an NCI-60 human cancer cell lines panel. We have shown that the replacement of 3,4,5-trimethoxyphenyl A-ring of phenstatin with 2,4,5-trifluoro-3-methoxyphenyl unit, results in the conservation of both antitubulin and cytotoxic effect. Fluoro isocombretastatin 7k was the most effective anticancer agent in the present study and demonstrated the highest antiproliferative potential on leukemia cell lines SR (GI50=15 nM) and HL-60(TB) (GI50=23 nM) and on melanoma cell line MDA-MB-435 (GI50=19 nM).

International audience; Previous investigations on the incubation of phenstatin with rat and human microsomal fractions revealed the formation of nine main metabolites. The structures of eight of these metabolites have been now confirmed by synthesis and their biological properties have been reported. Eaton's reagent was utilized as a convenient condensing agent, allowing, among others, a simple multigram scale preparation of phenstatin. Synthesized metabolites and related compounds were evaluated for their antiproliferative activity in the NCI-60 cancer cell line panel, and for their effect on microtubule assembly. Metabolite 23 (2'-methoxyphenstatin) exhibited the most potent in vitro cytotoxic activity: inhibition of the growth of K-562, NCI-H322M, NCI-H522, KM12, M14, MDA-MB-435, NCI/ADR-RES, and HS 578T cell lines with GI(50) values

Phosphonium salts (I) contain two functionalities to undergo both C—C bond formation through Wittig reaction with simple or functionalized aldehydes, and nucleophilic addition reactions with aryl/heteroarylmagnesium bromides to give diarylketones including novel analogues of phenstatin such as ketones (V).

Prostate cancer is ranked third among fatal cancers, after bronchial and colorectal cancers, with 150,000 deaths recorded in 2010. The design of new prostate cancer drugs should take into account : i) the metabolism which can alter the efficiency of an active compound in vivo, and ; ii) the individual differences in metabolism resulting from patients’ environments. Our study, in partnership with the HEI School of Lille, is concerned with Phenstatin (a compound in pre-clinical development) and its metabolites : indeed, promising therapeutic results have recently been obtained with taxanes in hormone-resistant prostate cancers which stabilize microtubules by inhibiting their depolymerization.The aim of this work was firstly to study the pharmacological effect of Phenstatin and its metabolites, obtained after biotransformation by human liver microsomes, on tubulin polymerization and the proliferation of human prostate cancer cells (PC3 cell line). Secondly, we attempted to determinate the CYPs responsible for the formation of the Phenstatin metabolites we have identified and quantified. Thirdly, we addressed the influence of environmental conditions, more specifically the presence of cadmium, on the metabolism of these novel compounds and their activity towards prostate cancer cells. In order to understand the response or non-response of different treatments, we determined expression profiles of genes involved in the metabolism of xenobiotics by using high throughput technology based on real time quantitative PCR (TaqmanTM Low Density Arrays). A study model was designed in order to show the effect of environmental factors on anticancer compounds’ efficiency. This model should subsequently be transposable to other agents involved in xenobiotic metabolism and reveal genetic or epigenetic mechanisms responsible for individuals’ responses to anticancer treatments., Le cancer de la prostate est la troisième cause de mortalité par cancer chez l’homme après les cancers colorectaux et broncho-pulmonaires avec, en 2010, près de 150 000 décès. On voit donc tout l’intérêt d’élaborer de nouvelles stratégies thérapeutiques en essayant de prendre en compte à la fois : i) la métabolisation qui peut modifier in vivo l’efficacité de la molécule initiale et ii) les différences individuelles intervenant à ce niveau du fait de la nature de l’environnement du patient.Nous avons porté notre étude, en collaboration avec l’Ecole HEI de Lille, sur l’intérêt de la Phenstatine (molécule en développement pré-clinique) et de ses métabolites puisque qu’au cours de ces dernières années des résultats thérapeutiques prometteurs ont été obtenus, dans les cancers prostatiques hormono-résistants avec les taxanes, dont le rôle est de stabiliser les microtubules en inhibant leur dépolymérisation.L’objectif de ce travail de thèse a donc été dans un premier temps d’étudier l’effet pharmacologique de la Phenstatine et de ses métabolites issus de sa biotransformation par des microsomes hépatiques humains sur la polymérisation de la tubuline ainsi que sur la prolifération de la lignée cancéreuse prostatique humaine PC3. Nous avons ensuite essayé de déterminer les CYPs responsables de la formation des métabolites identifiés et quantifiés. Enfin, nous avons abordé l’influence de certaines conditions environnementales, plus particulièrement la présence de cadmium, sur le métabolisme de ces composés originaux et donc sur leur activité vis-à-vis de cellules cancéreuses prostatiques. Pour tenter de comprendre la réponse ou la non réponse à ces différents traitements, nous avons suivi les profils d’expression de gènes impliqués dans la prise en charge cellulaire des xénobiotiques en utilisant une technologie fonctionnant à haut débit et basée sur le principe de la PCR quantitative en temps réel (TaqmanTM Low Density Arrays). Un modèle d’étude a pu ainsi être élaboré afin de montrer l’implication de l’environnement sur l’efficacité d’une molécule à visée anticancéreuse. Ce modèle devrait par la suite pouvoir être élargi à d’autres agents participant à la métabolisation des xénobiotiques et déboucher sur la mise en évidence des mécanismes génétiques ou épigénétiques responsables de ces réponses particulières aux traitements anticancéreux.

Phenstatin and its derivatives with the modified ring A have been synthesized, using plant allylpolyalkoxybenzenes as a starting material. The targeted molecules were evaluated in a phenotypic sea urchin embryo assay for antiproliferative activity. It was found that phenstatin ring A modifications yielded antimitotic compounds. The most effective myristicin derivative 7d (combretastatin A-2 analogue) was determined to be ca. 10 times more potent than phenstatin, displaying antimitotic tubulin-destabilizing activity at the same concentration range as combretastatins. In contrast to combretastatins, 7d featured the steric stability with potential for further design as anticancer agent.