Potansiyel antibiyotik ve antitümör özelliklere sahip yeni ferrosen türevlerinin tasarım ve sentezi

TÜBİTAK TBAG01.10.2008Ferrosen ve ferrosenyum tuzlarının son yapılan çalışmalarda antitümör aktivite göstermesinden sonra yapılarında ferrosen grubu ihtiva eden biyoaktif yapılar büyük önem kazanmıştır çünkü ferrosen grubu bu bileşiklerin sahip oldukları antitümör ve antibiyotik etkileri dahada artırmaktadır. Dolayısıyla daha etkili antitümör maddelerinin bulunması ve geliştirilmesi kanser gibi hastalıkların tedavisinde yeni umutlar olabilir. Organik ve organometalik bileşiklerin biyolojik aktiviteleri hakkında bazı tahminler yapılabilmekle beraber aktivitelerin kesin olarak belirlenmesi ancak biyolojik aktivite testleri ile mümkündür. Bu da genellikle bu bileşiklerin önce eldesini yani laboratuvarda sentezini gerektirmektedir. Bir ferrosenil grubunun antitümör ve antibiyotik gibi önemli biyolojik aktivitelere sahip alkilidensiklopentendion (1), siklopentenon (2), sikloheptadienon (3) ve pirazol (4) yapılarına direk bağlı olduğu bu tür türevler literatürde hemen hemen bilinmemekte ve bunların sentezine yönelik herhangi bir çalışmada yoktur. Bu projede yeni ve uygulanabilir yöntemler geliştirilerek yapıları aşağıda gösterilen literatürde bilinmeyen bu yeni ferrosenii türevlerinin sentezi gerçekleştirilmiştir. Ferrosenil grubunun bu maddelerin sahip oldukları biyolojik aktiviteyi dahada artırması beklenmektedir. Sentezlenen bu bileşiklerden bir veya bir kaçının istenilen düzeyde biyolojik aktivite göstermesi halinde bu bileşikler kanser gibi hastalıkların tedavisinde umut verici yeni ilaç maddeleri olabileceklerdir.After ferrocene and ferrocenium salts have shown antitumor activities in recent studies, biologically active compounds containing a ferrocene moiety have gained more importance since the ferrocene group increases their antitumor and antibiotic activities more and more. Development of new potential antitumor compounds is likely to provide new promising drug substances for curing the cancer type diseases. Although the biological activities of organic and organometallic compounds/complexes can be predicted to some extent, the certain activities can be determined only by their biological activity tests, which would require first the laboratory synthesis of such compounds/complexes. The examples of ferrocenyl-substituted alkylidenecyclopentenediones (1), cyclopentenones (2), cycloheptadienones (3) and pyrazoles (4), as well as general methods for their syntheses, are almost unknown, but these compounds should be medicinally very important compounds. In this project, the synthesis of these new compounds, which are unknown in literature, was achieved by developing new and applicable methods. It is expected that ferrocenyl moiety will increase their current biological activity more and more. If one or few of them shows the expected biological activity, then such compounds can be promising drug candidates to cure the cancer type diseases

Atypical McMurry Cross-Coupling Reactions Leading to a New Series of Potent Antiproliferative Compounds Bearing the Key [Ferrocenyl-Ene-Phenol] Motif

In the course of the preparation of a series of ferrocenyl derivatives of diethylstilbestrol (DES), in which one of the 4-hydroxyphenyl moieties was replaced by a ferrocenyl group, the McMurry reaction of chloropropionylferrocene with a number of mono-aryl ketones unexpectedly yielded the hydroxylated ferrocenyl DES derivatives, 5a–c, in poor yields (10%–16%). These compounds showed high activity on the hormone-independent breast cancer cell line MDA-MB-231 with IC50 values ranging from 0.14 to 0.36 µM. Surprisingly, non-hydroxylated ferrocenyl DES, 4, showed only an IC50 value of 1.14 µM, illustrating the importance of the hydroxyethyl function in this promising new series. For comparison, McMurry reactions of the shorter chain analogue chloroacetylferrocene were carried out to see the difference in behaviour with mono-aryl ketones versus a diaryl ketone. The effect of changing the length of the alkyl chain adjacent to the phenolic substituent of the hydroxylated ferrocenyl DES was studied, a mechanistic rationale to account for the unexpected products is proposed, and the antiproliferative activities of all of these compounds on MDA-MB-231 cells lines were measured and compared. X-ray crystal structures of cross-coupled products and of pinacol-pinacolone rearrangements are reported.The authors wish to thank P. Herson and J. Vaissermann for three crystal structure determinations and T. Cresteil for IC50 determinations. We thank Anh N’Guyen for full discussions. K.K.’s stay in Paris was supported through an European Community Marie Curie Fellowship (HMPT-CT-2000- 00186). We thank the Agence Nationale de la Recherche for financial support (ANR 2010 BLAN 7061 blanc “Mecaferrol”) and the Ministère des Affaires Etrangères for a doctoral fellowship (M.G.)

Ferrosenil sübstitüe pirazollerin sentezi

Pyrazoles have been studied for over a century as an important class of heterocyclic compounds and continue to attract considerable interest due to the broad range of biological activities they possess. The incorporation of the essential structural features of pyrazoles with a ferrocene moiety could provide new derivatives with unexpected and/or enhanced biological activities since several ferrocene derivatives have already been shown to be active against a number of tumors. For this reason, we investigated the synthesis of ferrocenyl-substituted pyrazoles, such as 1-alkyl/aryl-5-ferrocenylpyrazoles, by employing the reaction between (2-formyl-1-chlorovinyl)ferrocene and hydrazine derivatives. Although this reaction is known, it was not studied in much detail and the low yields of ferrocenyl pyrazoles were obtained. Thus, we have reinvestigated this reaction and improved the yields of pyrazoles by optimizing the reaction conditions. (2-Formyl-1-chloro vinyl)ferrocene was first reacted with the excess amount (3 equivalents) of hydrazine derivative at 25 0C in dioxane under argon for 2 hours, and the resulting mixture was then heated at 100 0C for 6 hours in the same solvent. Under our optimized conditions, these reactions afforded 1-alkyl/aryl-5-ferrocenylpyrazole derivatives in moderate to good yields as a single or major product of the reaction. In some cases, 1-alkyl/aryl-3-ferrocenylpyrazole derivatives resulted from these reactions as very minor products.M.S. - Master of Scienc

Synthèse de composés organométalliques de la série du ferrocénophane et évaluation de leurs activités antiprolifératives sur les cellules du cancer du sein et de la prostate

The development of organometallic compounds for cancer therapeutics is one of the most quickly growing areas of bioorganometallic chemistry. Among organometallic compounds based on endocrine modulators, the most active and well-studied are the ferrocenyl derivatives of tamoxifen, developed by the Jaouen group. Ferrocifen and ferrociphenol are very active against both hormone dependent (MCF-7) and hormone independent (MDA-MB-231) breast cancer cells. Ferrocenophanyl diphenol, an analogue of ferrociphenol, has been found much more active than this latter compound. The objective of the present work is to study the synthesis and the antitumor activity of ferrocenophane series. Most of new compounds that were prepared are 1-(diarylmethylidene)-[3]ferrocenophanes bearing one or two substituents (R1, R2 = H, OH, OAc, NH2, NHAc, Br, CN, NHCO(CH2)2NMe2, O(CH2)3NMe2 or O(CH2)2COOEt) on the para position of the aryl group. These compounds confirm the high antitumor activity of the ferrocenophane series compared to the ferrocene series. Pinacols and pinacolic rearrangement compounds were studied; they were obtained from a McMurry coupling reaction. Pinacols showed high antitumor activity against MDA-MB-231 cells while the pinacolic rearrangement compounds are less active. This work shows clearly that the ferrocenophane series is more active than the ferrocene series against hormone-independent breast cancer cells.L'utilisation de composés organométalliques pour le traitement des cancers est l'un des domaines de la chimie bioorganométallique qui connait une expansion rapide. Parmi les composés développés en endocrinologie, les composés les plus intéressants et très étudiés sont les dérivés ferrocéniques du tamoxifène. Ils sont développés par le groupe du Professeur Gérard Jaouen. Parmi ces composés, le ferrocifène et le ferrociphénol sont très actifs contre les cellules cancéreuses hormono-dépendantes (MCF-7) et hormono-indépendantes (MDA-MB-231) du cancer du sein. Le ferrocénophanyl diphénol, un dérivé phénolique de la série ferrocénophane et analogue du ferrociphénol, s'est montré plus actif que celui-ci. Dans le but de verifier cette caractéristique et aussi de trouver de meilleures molécules, de nouveaux composés de la série ferrocénophane ont été synthétisés et étudiés. Les nouveaux composés sont des 1-(diarylméthylidène)-[3]ferrocénophanes, portant un ou deux substituants (R1, R2 = H, OH, OAc, NH2, NHAc, Br, CN, NHCO(CH2)2NMe2, O(CH2)3NMe2 ou O(CH2)2COOEt) en para du cycle aromatique. L'activité antitumorale de ces composés prouve que la série des ferrocenophanes est plus efficace que la série des ferrocènes contre les cellules cancéreuses du sein. Les études ont été également menées sur les pinacols et les produits résultant de l'arrangement pinacolique. Ces deux produits ont été péparés à partir de la réaction de couplage de McMurry. On trouve que les pinacols sont très actifs contre les cellules cancéreuses MDA-MB-231. Cependant les produits de transposition sont peu réactifs. Ce travail montre que la série des ferrocénophanes est plus efficace que la série des ferrocènes contre les céllules cancéreuses du sein

Conception, Synthesis, Characterization and Antimicrobial Evaluation of New Ferrocene-Based Derivatives Inspired by the Bisacodyl Lead Structure

Abstract: The antibacterial activity of bisacodyl, a drug used in therapeutic as laxative, and its ferrocenyl analogues was investigated against Gram-positive and Gram-negative foodborne pathogens including Listeria monocytogenes, Escherichia coli, Enterococcus faecalis, Salmonella enterica, Micrococcus luteus and Staphylococcus aureus. The results showed that most of these compounds exhibit an excellent antimicrobial activity, and the bisacodyl analogues seemed to be more bactericides than bacteriostatic

Conception, synthesis, characterization and antimicrobial evaluation of new ferrocene-based derivatives inspired by the bisacodyl lead structure.

International audienc

Tandem aza-Michael/spiro-ring closure sequence: access to a versatile scaffold and total synthesis of (±)-coerulescine

International audienc

Facile synthesis and strong antiproliferative activity of disubstituted diphenylmethylidenyl-[3]ferrocenophanes on breast and prostate cancer cell lines

International audienceA series of new 1-[di-(4-R-phenyl)-methylidenyl)]-[3]ferrocenophanes, where R = OH, NH2, NHAc, and the phenyl substitution is mixed or identical, are highly antiproliferative against MDA-MB-231 and PC-3 cancer cells, with IC50 values ranging from 0 05-5 6 mu M on MDA-M B-231 and 0 02-12 5 mu M on PC-

Efficacy of a novel ferrocenyl diaryl butene citrate compound as a biocide for preventing healthcare-associated infections

International audienceThe antiseptic and disinfectant potential of a formulation containing the tamoxifen analogue 1,1-bis[4-(3-dimethylaminopropoxy)phenyl]-2-ferrocenyl-but-1-ene citrate was assessed according to European standards and pharmacopeia in comparison with a commercial antiseptic product containing hexamidine diisethionate, chlorhexidine digluconate and chlorocresol as active ingredients. The formulation met the phase 1 requirement of reducing by 5 cycles the counts of microorganisms frequently involved in healthcare-associated infections, namely Escherichia coli ATCC 10536, Pseudomonas aeruginosa ATCC 15442, Staphylococcus aureus ATCC 6538, Enterococcus hirae ATCC 10541 and Candida albicans ATCC 10231. It also killed a clinical isolate of Acinetobacter baumannii which is highly resistant to antibiotics and antiseptics. In phase 2/step 2 tests, it reduced the counts of E. coli ATCC 10536 by 4 log cycles within 60 seconds on hands (standard EN 1499). The novel formula is a potent biocide, and this demonstration could lead to the development of a new commercial antiseptic