Design and preparation of pH-sensitive cytotoxic liposomal formulations containing antitumor colchicine analogues for target release.

Herein, we describe the synthesis of pH-sensitive lipophilic colchicine prodrugs for liposomal bilayer inclusion, as well as preparation and characterization of presumably stealth PEGylated liposomes with above-mentioned prodrugs. These formulations liberate strongly cytotoxic colchicinoid derivatives selectively under slightly acidic tumor-associated conditions, ensuring tumor-targeted delivery of the compounds. The design of the prodrugs is addressed to pH-triggered release of active compounds in the slight acidic media, that corresponds to tumor microenvironment, while keeping sufficient stability of the whole formulation at physiological pH.

Design of an aryne-platform for the synthesis of non-racemic heterocyclic allocolchicinoids.

A four-step semisynthetic approach towards a highly versatile allocolchicine-related chiral aryne intermediate starting from naturally occurring colchicine was developed, and some of its synthetic transformations were studied. The generated benzyne intermediate afforded a number of non-racemic heterocyclic allocolchicinoids, which were shown to exhibit potent cytotoxicity towards COLO 357, OSA and Raji cells. The proposed methodology is attractive for the synthesis of libraries of new cytotoxic tubulin inhibitors.

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.

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.

Synthesis, Molecular Docking, In Vitro and In Vivo Studies of Novel Dimorpholinoquinazoline-Based Potential Inhibitors of PI3K/Akt/mTOR Pathway.

A (series) range of potential dimorpholinoquinazoline-based inhibitors of the was synthesized. Several compounds exhibited cytotoxicity towards a panel of cancer cell lines in the low and sub-micromolar range. Compound with the highest activity and moderate selectivity towards MCF7 cells which express the mutant type of PI3K was also tested for the ability to inhibit PI3K-(signaling pathway) downstream effectors and associated proteins.

Liposomal Formulation of a PLA2-Sensitive Phospholipid-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.

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

Two 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.

Colchicine Alkaloids and Synthetic Analogues: Current Progress and Perspectives.

Colchicine, the main alkaloid of , 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 first coordination polymers with an [O][N]P(S)-Hg segment: a combined experimental, theoretical and database study.

The study of one-dimensional coordination polymers {HgClL} (1), {HgBrL} (2) and {HgClL} (3) (L = (S)P(OCH)NHCHNHP(S)(OCH) and L = (S)P(OCH)NCHNP(S)(OCH)) is the first such structural study of Hg(ii) coordination polymers with (O)(N)PS-based ligands. The mercury atoms adopt a distorted trigonal pyramidal environment, Hg(Cl)(S) for 1 and 3 and Hg(Br)(S) for 2, and the difference observed in the stoichiometry of mercury halide to the thiophosphoramide ligand in 1 and 3 with respect to the one in 2 is a result of the formation of the HgCl ring, however, the molar ratio 2 : 1 of HgX (X = Cl and Br) to ligand was used for the preparation of all three complexes. The strengths of mercury-sulfur and mercury-halide covalent bonds are evaluated by theoretical calculations (QTAIM and NBO) which show their principally electrostatic nature with a partial covalent contribution.

The (CFC(O)NH)(CHCHNH)P(O) phosphoric triamide as a novel carrier with excellent efficiency for Cu(ii) in a liquid membrane transport system.

Transport of Ag(i), Cd(ii), Co(ii), Cu(ii), Ni(ii), Pb(ii) and Zn(ii) cations across a bulk liquid membrane (BLM) containing ,'-dibenzyl--(2,2,2-trifluoroacetyl)-phosphoric triamide (PTC) as a new carrier is studied by atomic absorption spectrometry. The results show selective and efficient transport of the copper(ii) cation from aqueous solution in the presence of the other cations. Various factors are optimized in order to obtain maximum transport efficiency.

Phospholipidic Colchicinoids as Promising Prodrugs Incorporated into Enzyme-Responsive Liposomes: Chemical, Biophysical, and Enzymological Aspects.

Enzyme-responsive liposomes release their cargo in response to pathologically increased levels of enzymes at the target site. We report herein an assembly of phospholipase A2-responsive liposomes based on colchicinoid lipid prodrugs incorporated into lipid bilayer of the nanosized vesicles. The liposomes were constructed to addresses two important issues: (i) the lipid prodrugs were designed to fit the structure of the enzyme binding site; and (ii) the concept of lateral pressure profile was used to design lipid prodrugs that introduce almost no distortions into the lipid bilayer packing, thus ensuring that corresponding liposomes are stable.

Evaluation of N-H...S and N-H...π interactions in O,O'-diethyl N-(2,4,6-trimethylphenyl)thiophosphate: a combination of X-ray crystallographic and theoretical studies.

In the crystal structure of O,O'-diethyl N-(2,4,6-trimethylphenyl)thiophosphate, CHNOPS, two symmetrically independent thiophosphoramide molecules are linked through N-H...

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

Two novel indole-containing allocolchicinoids were prepared from naturally occurring colchicine 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: IC < 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.