A Facile Synthetic Approach to Nonracemic Substituted Pyrrolo-allocolchicinoids Starting from Natural Colchicine

A six-step semisynthetic approach towards chiral nonracemic pyrrolo-allocolchicinoids starting from naturally occurring colchicine was developed. The synthetic scheme includes an electrocyclic tropolone ring contraction to afford allocolchicinic acid followed by the Curtius reaction, giving the corresponding aniline. The Sandmeyer reaction and copper-mediated hydrazination gave hydrazine-substituted allocolchicine. This was introduced into the Fischer indole synthesis, affording libraries of regioisomeric indole-based allocolchicine congeners

Colchicine Alkaloids and Synthetic Analogues: Current Progress and Perspectives

Colchicine, the main alkaloid of Colchicum autumnale, is one of the most famous natural molecules. Although colchicine belongs to the oldest drugs (in use since 1500 BC), its pharmacological potential as a lead structure is not yet fully exploited. This review is devoted to the synthesis and structure-activity relationships (SAR) of colchicine alkaloids and their analogues with modified A, B, and C rings, as well as hybrid compounds derived from colchicinoids including prodrugs, conjugates, and delivery systems. The systematization of a vast amount of information presented to date will create a paradigm for future studies of colchicinoids for neoplastic and various other diseases

Design, Synthesis and In Vitro Biological Activity of Novel C-7 Methylene Congeners of Furanoallocolchicinoids

A series of novel heterocyclic colchicine derivatives bearing a C-7 methylene fragment were synthesized via Wittig, Horner–Wadsworth–Emmons and Nenajdenko–Shastin olefination approaches. The in vitro biological activities of the most promising compounds were investigated using MTT assays and cell cycle analyses. Compounds with an electron withdrawing group on the methylene fragment exhibited substantial antiproliferative activity towards COLO-357, BxPC-3, HaCaT, PANC-1 and A549 cell lines. The spatial orientation of the substituent at the double bond significantly influenced its biological activity

Synthesis of Nonracemic Pyrrolo-allocolchicinoids Exhibiting Potent Cytotoxic Activity

An efficient eight-step semisynthetic approach towards nonracemic pyrrolo-allocolchicinoids starting from natural colchicine was developed by exploiting Pd-catalyzed domino Sonogashira coupling/5-endo-dig cyclization of a 2-iodo-trifluoroacetanilide intermediate to build up the heterocyclic ring system. The N-Me substitution of the pyrrole ring enhanced the antitumor activity of the prepared molecules by 2-3 orders of magnitude. Among the active compounds, the N-methylated colchicinoid exhibited powerful cytotoxic and antiproliferative properties at concentrations < 1 nM

Competitor hydrogen-bond acceptors in the SP(NH)3-based structures: Comparison of structural features – Computational/database and experimental

The phosphorothioic triamides (4-Cl-CHCHNH)P(S) (I) and (4-CH-CHCHNH)P(S) (II) were synthesized to study their coordination behaviors towards Hg(II) cation. The resulting complexes, [(4-Cl-CHCHNH)P(S)]HgCl (III) and [(4-CH-CHCHNH)P(S)]HgCl (IV), are the first examples of mercury complexes with SP(NHR) ligands characterized by X-ray crystallography. The presence of NH/CH units and some potential competitor acceptors with moderate/weak acceptor capabilities (sulfur, chlorine and π system) provides the opportunity to study the hydrogen bond elements of (I), (III) and (IV), structurally and of all four compounds theoretically. The strengths of inter- and intramolecular hydrogen bonds were assessed by quantum chemical calculations (Atoms In Molecules (AIM), and Natural Bond Orbital (NBO)), and the internal interactions were further examined by reduced density gradient (RDG) analysis. The differences/similarities of structures were addressed in the view point of geometry, conformations related to flexible substituted benzyl moieties, crowding in the structures and non-bonded contacts, stabilization of four-membered HgCl rings and some topics related to solution nuclear magnetic resonance studies (chemical shifts and coupling constants). The similarity of structures investigated allowed for a precise assignment of vibrational frequencies. A survey of the Hg—S[dbnd]P segment in the Cambridge Structural Database shows that the Hg—S bond lengths in (III) and (IV) are among the smallest Hg—S bonds in the structures with the thiophosphoryl-holding ligands.Support of this investigation by Ferdowsi University of Mashhad (project numbers 53938/3 and 33271/3) is gratefully acknowledged. The authors appreciatively would like to thank the Cambridge Crystallographic Data Centre for access to the CSD Enterprise. We acknowledge X-ray Diffraction and Bio-SAXSCore Facility of CIISB, Instruct-CZ Centre, supported by MEYS CR (LM2018127)

Liposomal Formulation of a PLA2-Sensitive Phospholipid&ndash;Allocolchicinoid Conjugate: Stability and Activity Studies In Vitro

To assess the stability and efficiency of liposomes carrying a phospholipase A2-sensitive phospholipid-allocolchicinoid conjugate (aC-PC) in the bilayer, egg phosphatidylcholine and 1-palmitoyl-2-oleoylphosphatidylglycerol-based formulations were tested in plasma protein binding, tubulin polymerization inhibition, and cytotoxicity assays. Liposomes L-aC-PC10 containing 10 mol. % aC-PC in the bilayer bound less plasma proteins and were more stable in 50% plasma within 4 h incubation, according to calcein release and FRET-based assays. Liposomes with 25 mol. % of the prodrug (L-aC-PC25) were characterized by higher storage stability judged by their hydrodynamic radius evolution yet enhanced deposition of blood plasma opsonins on their surface according to SDS-PAGE and immunoblotting. Notably, inhibition of tubulin polymerization was found to require that the prodrug should be hydrolyzed to the parent allocolchicinoid. The L-aC-PC10 and L-aC-PC25 formulations demonstrated similar tubulin polymerization inhibition and cytotoxic activities. The L-aC-PC10 formulation should be beneficial for applications requiring liposome accumulation at tumor or inflammation sites

Discovery of dihydrofuranoallocolchicinoids - Highly potent antimitotic agents with low acute toxicity

International audienceTwo series of heterocyclic colchicinoids bearing β-methylenedihydrofuran or 2H-pyran-2-one fragments were synthesized by the intramolecular Heck reaction. Methylenedihydrofuran compounds 9a and 9h were found to be the most cytotoxic among currently known colchicinoids, exhibiting outstanding antiproliferative activity on tumor cell lines in picomolar (0.01-2.1 nM) range of concentrations. Compound 9a potently and substoichiometrically inhibits microtubule formation in vitro, being an order of magnitude more active in this assay than colchicine. Derivatives 9a and 9h revealed relatively low acute toxicity in mice (LD50 ≥ 10 mg/kg i.v.). The X-Ray structure of colchicinoid 9a bound to tubulin confirmed interaction of this compound with the colchicine binding site of tubulin

Synthesis and biological evaluation of novel non-racemic indole-containing allocolchicinoids

Two novel indole-containing allocolchicinoids were prepared from naturally occurring coichicine exploiting the Curtius rearrangement and tandem Sonogashira coupling/Pd-catalyzed cyclization as the key transformations. Their cytotoxic properties, apoptosis-inducing activity, tubulin assembly inhibition and short-time cytotoxic effects were investigated. Compound 7 demonstrated the most pronounced anti-cancer activity: IC50 < 1 nM, cell cycle arrest in the G2/M phase, 25% apoptosis induction, as well as lower destructive short-time effects on HT-29 cell line in comparison with colchicine. Docking studies for prepared indole-derived allocolchicine analogues were carried out. (C) 2017 Elsevier Masson SAS. All rights reserved

Design, Synthesis and In Vitro Investigation of Cabozantinib-Based PROTACs to Target c-Met Kinase

(1) Background: This investigation aimed at developing a series of c-Met-targeting cabozantinib-based PROTACs. (2) Methods: Purification of intermediate and target compounds was performed using column chromatography, in vitro antiproliferation activity was measured using a standard MTT assay and a c-Met degradation assay was performed via the immunoblotting technique. (3) Results: Several compounds exhibited antiproliferative activity towards different cell lines of breast cancer (T47D, MDA-MB-231, SKBR3, HCC1954 and MCF7) at the same level as parent cabozantinib and 7-demethyl cabozantinib. Two target conjugates, bearing a VHL-ligand as an E3-ligase binding moiety and glycol-based linkers, exhibited the effective inhibition of c-Met phosphorylation and an ability to decrease the level of c-Met in HCC1954 cells at micromolar concentrations. (4) Conclusions: Two compounds exhibit c-Met inhibition activity in the nanomolar range and can be considered as PROTAC molecules due to their ability to decrease the total level of c-Met in HCC1954 cells. The structures of the offered compounds can be used as starting points for further evaluation of cabozantinib-based PROTACs