ABSTRACT
Epothilones are 16-membered macrolides that can act as microtubule-targeting agents to tackle cancer. Many synthetic analogues have been investigated for their activity, yet often based on macrolide structures. A notable exception is Ixabepilone, an azalide representing the only epothilone-like molecule approved by the FDA as a chemotherapeutic. Exploiting the amide-triazole bioisosterism, in this work we report the synthesis of the first generation of epothilones lacking the macrolide or azalide structure, with the ester or amide linkage replaced by a triazole unit. Together with the synthesis of this new analogue, computational and biological evaluations have been performed too.
ABSTRACT
The design of artificial enzymes has emerged as a promising tool for the generation of potent biocatalysts able to promote new-to-nature reactions with improved catalytic performances, providing a powerful platform for wide-ranging applications and a better understanding of protein functions and structures. The selection of an appropriate protein scaffold plays a key role in the design process. This review aims to give a general overview of the most common protein scaffolds that can be exploited for the generation of artificial enzymes. Several examples are discussed and categorized according to the strategy used for the design of the artificial biocatalyst, namely the functionalization of natural enzymes, the creation of a new catalytic site in a protein scaffold bearing a wide hydrophobic pocket and de novo protein design. The review is concluded by a comparison of these different methods and by our perspective on the topic.
Subject(s)
Metalloproteins , Metalloproteins/chemistry , Protein Engineering/methods , Catalytic Domain , Catalysis , Enzymes/metabolismABSTRACT
Withanolides constitute a well-known family of plant-based alkaloids characterised by widespread biological properties, including the ability of interfering with Hedgehog (Hh) signalling pathway. Following our interest in natural products and in anticancer compounds, we report here the synthesis of a new class of Hh signalling pathway inhibitors, inspired by withaferin A, the first isolated member of withanolides. The decoration of our scaffolds was rationally supported by in silico studies, while functional evaluation revealed promising candidates, confirming once again the importance of natural products as inspiration source for the discovery of novel bioactive compounds. A stereoselective approach, based on Brown chemistry, allowed the obtainment and the functional evaluation of the enantiopure hit compounds.
Subject(s)
Antineoplastic Agents , Withanolides , Antineoplastic Agents/pharmacology , Hedgehog Proteins/pharmacology , Signal Transduction , Withanolides/pharmacologyABSTRACT
The first total synthesis of chondrochlorenâ A is accomplished using a 1,2-metallate rearrangement addition as an alternative for the Nozaki-Hiyama-Kishi reaction. This transformation also avoids the inherent challenges of this polyketide segment and provides a new, unprecedented strategy to assemble polyketidal frameworks. The formation of the Z-enamide is accomplished using a Z-selective cross coupling of the corresponding amide to a Z-vinyl bromide.
ABSTRACT
The aza-alkylation reaction at indole's C3 position allows the introduction of a differently substituted aminomethyl group, with the formation of a new stereogenic centre. The reaction involves essentially three different partners: an indole, aldehyde and amine. The formation of the reactive iminium species can be catalyzed by metals, Brønsted acids, Lewis acids or organocatalysts. The stereoselective reaction is feasible with satisfactory outcomes. This review summarizes the recent (2000-2019) meaningful papers in which the in-depth study and exploitation of this reactivity are reported.
ABSTRACT
The piperidine ring is a widespread motif in several natural bioactive alkaloids of both vegetal and marine origin. In the last years, a diversity-oriented synthetic (DOS) approach, aimed at the generation of a library of piperidine-based derivatives, was developed in our research group, employing commercially available 2-piperidine ethanol as a versatile precursor. Here, we report the exploration of another ramification of our DOS approach, that led us to the stereoselective total synthesis of (-)-anaferine, a bis-piperidine alkaloid present in Withania somnifera extract. This natural product was obtained in 9% overall yield over 13 steps, starting from a key homoallylic alcohol previously synthesised in our laboratory. Therefore, the collection of piperidine-derivatives accessible from 2-piperidine ethanol was enriched with a new, diverse scaffold.
Subject(s)
Alkaloids/chemistry , Alkaloids/chemical synthesis , Piperidines/chemistry , Withania/chemistry , Ethanol/chemistry , Plant Extracts/chemistry , StereoisomerismABSTRACT
Four different hybrid compounds have been efficiently synthesized by conjugation of deacetylthiocolchicine with pironetin-inspired derivatives. The modest bioactivity and the apparent absence of interaction with α-tubulin is explained by a posteriori in silico investigation, which suggests a relevant distance between the thiocolchicine binding site and the proper pocket on the α-tubulin. The modest activity on resistant cells suggested that the lipophilic nature of the linker used renders the resulting compounds better substrates for p-Gp efflux pumps. The study better clarifies the design of bivalent compounds that target hetero tubulin/microtubules.
Subject(s)
Antineoplastic Agents/chemical synthesis , Colchicine/analogs & derivatives , Tubulin/metabolism , Antineoplastic Agents/pharmacology , Binding Sites , Cell Line, Tumor , Cell Proliferation/drug effects , Colchicine/chemistry , Colchicine/metabolism , Humans , Ligands , Molecular Dynamics Simulation , Stereoisomerism , Tubulin/chemistryABSTRACT
1,2,3-Triazole is a well-known scaffold that has a widespread occurrence in different compounds characterized by several bioactivities, such as antimicrobial, antiviral, and antitumor effects. Moreover, the structural features of 1,2,3-triazole enable it to mimic different functional groups, justifying its wide use as a bioisostere for the synthesis of new active molecules. Here, we provide an overview of the 1,2,3-triazole ring as a bioisostere for the design of drug analogs, highlighting relevant recent examples.