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Titolo/Abstract/Parole chiave

Synthetic approaches to novel derivatives of natural hemiasterlins and epothilone B as potential anticancer drugs interfering with microtubule dynamics

Rullo, Cinzia (2011) Synthetic approaches to novel derivatives of natural hemiasterlins and epothilone B as potential anticancer drugs interfering with microtubule dynamics. Tesi di Dottorato , Università degli Studi di Ferrara.

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    Cancer is a disease characterized by uncontrolled growth of a group of cells that eludes physiologic turnover mechanisms. Conventional cytotoxic therapies of cancer often suffer from a lack of specificity, as they present low therapeutic index and considerable toxicity to healthy organs. Moreover, many kinds of cancer develop resistance to drugs and that is the most important factor in the failure of many chemotherapic treatments. Most of the effective anticancer drugs currently administered, as those at the moment in clinical trials are derived from natural products which are considered “lead compounds” in drug discovery process. Dynamic microtubules are among the most successful targets of anticancer drugs, as they are involved in chromosomes segregation during cell division. Microtubules-interacting agents can be divided into two different functional classes: from one side compounds which stabilize microtubules and those which inhibit the assembly of tubulin heterodimers. Hemiasterlins are member of a recently discovered family of natural tripeptides, isolated from marine sponge and containing three highly modified aminoacids which are responsible of their stability and in vivo activity. These compounds disrupt spindle microtubules, inhibit its growth and induce the self-association of tubulin dimers into single-walled rings and spirals. In order to circumvent the P-glycoprotein-mediated resistance of hemiasterlin, taltubulin (HTI-286, 1), an analogue where a phenyl group replaces the indole ring of hemiasterlin, was recently synthetized thanks to SAR studies. Based on its interesting biologic profile, we have thought to invert the aromatic ring with the methyl group on nitrogen at N-terminus aminoacid of HTI-286, with the aim to obtain a series of compounds with a biological activity better than parent compound, and easily synthesizable 3. We exploited the well-known potentiality of silver oxide as promoter in stereoselective nucleophilic substitution reaction of bromo-acylpeptides, affording a small group of tripeptides structurally variable in the perspective of a preliminary biological evaluation. Some compounds showed potent biological activity as growth inhibitors of some cancer cells lines and tubulin polymerization inhibitors. A future approach has also been envisaged to overcome the disadvantage related to cancer therapy toxicity, namely the selective delivery of drugs to the tumor site, by the conjugation of a drug with a proper carrier. Among the microtubules stabilizing agents, epothilones are a promising class of drugs, effective in particular solid tumor. Epothilones contain a 16-membered macrolide ring with a methylthiazole side chain and based on SAR data, not all modification are possible to obtained active compounds. ZK-EPO B (5), a benzothiazole analogue of EPO B (4), has an interesting biological profile and encouraged by its progress in clinical trials, the group of Prof. Altmann (where I spent 9 months during my Ph. D.) has thought to synthesize an analogue of EPO B (6), provided with a functional handle, at position 22 for antibody conjugation, a further modification was directed to the natural 12,13-epoxide moiety has been replaced by a cyclopropane ring. This modification eliminates potential problems of chemical and/or metabolic stability linked to the epoxide function; moreover the cyclopropane doesn’t lead to any loss of antiproliferative activity. The aim of my project was the synthesis of a cyclopropanated intermediate (7), whose desired stereoselectivity was the basis to decide the future of the project, installing at the same time the synthetic route of a heterocyclic core of new EPO B analogs. It was observed that Charette cyclopropanation of an unsubstituted allylic alcohol in the Northern part of the macrocycle was high selective (90:1), but the presence of a methyl at the double bond (C12) decreased the selectivity. A diastereomeric ratio ~ 20 :1 in favour of the right diastereoisomer was tolerated to carry on the whole synthesis and as regarding my project, the outcome of this reaction was acceptable (dr 15:1). Another challenge was the aldol reaction to install the chiral centre at position 15 of the macrocycle. This was accomplished thanks to Evans oxazolidinone chemistry.

    Tipologia del documento:Tesi di Dottorato (Tesi di Dottorato)
    Data:14 Marzo 2011
    Relatore:Simoni, Daniele
    Coordinatore ciclo:Manfredini, Stefano
    Istituzione:Università degli Studi di Ferrara
    Struttura:Dipartimento > Scienze farmaceutiche
    Soggetti:Area 03 - Scienze chimiche > CHIM/08 Chimica farmaceutica
    Parole chiave:Microtubules, Anticancer Drugs, Pro Drug, Hemiasterlin, Epothilone B
    Depositato il:13 Apr 2012 14:56


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