Synthesis of Pironetin–Dumetorine Hybrids as Tubulin Binders

Abstract

The synthesis of the eight stereoisomers of 6-[2-methoxy-3-(piperidinyl)propyl]-5,6-dihydropyran-2-one is reported. The configuration at C2′ and C6 is induced by a sterecontrolled allylation reaction with DIP-Cl. The general structure is the result of merging the structures of two natural products (pironetin and dumetorine) with the aim of discovering a new scaffold for tubulin binders. Docking studies and biological evaluations confirm the validity of the approach

Synthesis of Thicolchicine‐Based Conjugates: Investigation towards Bivalent Tubulin/Microtubules Binders

“…As active units, we choose thiocolchicine and hybrid compound 1 as models of β‐ and possible α‐binder, respectively (Figure ). Compounds 1 were recently designed in our laboratory, as the merging of two natural compounds, pironetin and dumetorine . Pironetin is an α‐tubulin binder, characterized by a δ‐unsaturated lactone, which serves as Michael acceptor for the Cys316 residue inside α‐tubulin binding site .…”

“…We took into consideration three of the eight prepared stereoisomers, in particular 1 a – c , for the synthesis of the new conjugate compounds on the base of their efficacy in giving stable and pure compounds. First, N ‐deacetyl‐10‐thiocolchicine 2 , deriving by acidic hydrolysis of thiocolchicine, was converted into compound 3 , exploiting a condensation with sebacic acid.…”

Stereodivergent Diversity‐Oriented Synthesis: Exploiting the Versatility of 2‐Piperidine Ethanol

“…[11] Allylmagnesium bromide (1 M solution in Et 2 O, 2.86 mL, 2.86 mmol) was added dropwise to a solution of (-)-DIP-Cl (1.06 g, 3.30 mmol) in anhydrous THF (13.5 mL), previously cooled to -78°C. Measures were collected at 20-25°C, using sodium D line wavelength λ=589 nm.…”

Total Synthesis of (–)-Anaferine: A Further Ramification in a Diversity-Oriented Approach

“…The idea of enriching our DOS library with (-)-anaferine was suggested by compound 3 (Scheme 1A), previously obtained in our laboratory as an intermediate in the synthesis of the pironetin-dumetorine hybrids shown in Figure 2 [15]. Compound 3 is characterised by a piperidine core, deriving from the 2-piperidine ethanol, by a 2-methoxy propane bridge and by a homoallylic alcohol.…”

“…In this project, the ideal starting point to achieve structural diversification proved to be the 2-piperidine ethanol (1), a cheap and commercially available racemic product that incorporates the fundamental highlighted 2-substituted-piperidine moiety. Our library is composed by natural products (such as aloperine, coniine, boehmeriasin A and sedum alkaloids [11][12][13][14]), and synthetic derivatives [15][16][17][18], as depicted in Figure 2. We are currently trying to further enrich our library with new scaffolds.…”