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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.

A (series) range of potential dimorpholinoquinazoline-based inhibitors of the PI3K/Akt/mTOR cascade was synthesized. Several compounds exhibited cytotoxicity towards a panel of cancer cell lines in the low and sub-micromolar range. Compound 7c 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. Compound 7c inhibited the phosphorylation of Akt, mTOR, and S6K at 125–250 nM. It also triggered PARP1 cleavage, ROS production, and cell death via several mechanisms. Inhibition of PI3Kα was observed at a concentration of 7b 50 µM and of 7c 500 µM and higher, that can indicate minority PI3Kα as a target among other kinases in the titled cascade for 7c. In vivo studies demonstrated an inhibition of tumor growth in the colorectal tumor model. According to the docking studies, the replacement of the triazine core in gedatolisib (8) by a quinazoline fragment, and incorporation of a (hetero)aromatic unit connected with the carbamide group via a flexible spacer, can result in more selective inhibition of the PI3Kα isoform.

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 50

A series of furan-based allocolchicinoids was prepared from commercially available colchicine via a nine-step reaction sequence. Cytostatic activity, cell cycle arrest, apoptosis, tubulin and F-actin expression were studied in vitro in 2D and 3D cultures of normal and tumor epithelial keratinocytes, endothelial and mesenchymal cells. Among the prepared furanoallocolchicine analogues, 14a and 7a displayed the most pronounced anti-cancer activity. These compounds induced two types of effects: (a) cell cycle arrest in the G2/M phase as a direct consequence of effective tubulin binding (metaphase effect), and (b) pronounced cell stress (as evidenced by the overexpression of tubulin and F-actin), which was caused by the hyperpolarization of mitochondrial and lysosomal membranes (interphase effect).

A new water-soluble conjugate, consisting of a chlorin-based photosensitizing part, and a 4-arylaminoquinazoline moiety with high potential affinity to an epidermal growth factor receptors (EGFR) and vascular endothelial growth factor receptors (VEGFR), suitable for photodynamic therapy (PDT), was synthesized starting from methylpheophorbide-a in seven steps. An increased accumulation of this compound in A431 cells with high level of EGFR expression, in comparison with CHO and HeLa cells with low EGFR expression was observed. The prepared conjugate exhibits dark and photoinduced cytotoxicity at micromolar concentrations with IC50dark/IC50light ratio of 11–18. In tumor-bearing mice, the conjugate preferentially accumulates in the tumor tissue.

Key step in the synthesis of the structural analogues (III) and (VI) of the antimitotic agent allocolchicine is the formation of the polycyclic ring system under Pd catalysis in the presence of CsOPiv, generated in situ.

A new method based on Negishi cross-coupling of alkenylzinc reagent (I) with aryl halides allows the synthesis of various Isocombretastatins.

Palladium-catalyzed coupling of 4-trifluoromethylsulfonyloxycoumarins la-d with heteroarylboronic acids 2a-d under the Suzuki reaction conditions affords 4-heteroaryl-substituted coumarins in good to excellent yields.

Thirteen novel analogues are prepared by Negishi cross-coupling of iodide (III) and aryl halides.

Colchicine-, allocolchicine-, and N-acetylcolchinol-derived azides are prepared and employed in Cu-catalyzed Huisgen—Sharpless cycloaddition (“click”) reactions with alkynes such as (III) and (IX) under microwave irradiation, thus opening access to libraries of C-7 modified colchicinoids (triazole derivatives).

Tris(ortho-tolyl)bismuth dichloride derivatives react with nucleophiles under basic conditions to give good to high yields of the C-arylated substrates. Under the same conditions, trimesitylbismuth dichloride affords only poor yields of the C-mesitylated substrates. Similar influence of the substitution pattern of tris(ortho-tolyl)bismuth diacetate derivatives was observed in the copper-catalysed arylation of hydroxyl or amino groups.

Triphenylbismuth diacetate reacts with various NH containing heteroarenes in the presence of a catalytic amount of copper diacetate to afford moderate to good yields of the N-phenylheteroarenes.

ortho -Halomethylphenyllead triacetates (halo=bromine or chlorine) react with phenols in the presence of triethylamine and a pyridine derivative to afford modest to good yields of dibenzo[ b , d ]-6 H -pyrans.

Palladium-catalyzed reactions of 4-(trifluoromethylsulfonyloxy)coumarins with amides and NH-heterocycles afforded 4-amido- and 4-(N-hetaryl)coumarins in 60-96% yield.

Several 2-(azidomethyl)arylboronic acids were synthesized. Their involvement into organolead-mediated Pinhey arylation reaction with 4-hydroxycoumarins afforded 3-[2-(azidomethyl)aryl]-4-hydroxycoumarins or [4,3-c]isoquinolino-coumarins in reasonable yields via two- or four-step one-pot reaction sequence. Palladium-catalyzed cross-coupling of organoboron reagents with 4-trifluoromethylsulfonyloxycoumarins under Suzuki reaction conditions gave 4-[2-(azidomethyl)aryl]coumarins in good yields. 2-(Azidomethyl)arylboronic acid, as well as azide-containing iso- and neoflavonoid compounds underwent catalytic alkyne-azide cycloaddition in THF-water, providing 1,4-triazole compounds regioselectively in good to excellent yields.

2-(methoxymethoxymethyl)aryllead triacetates, obtained in situ from the corresponding arylboronic acids, reacted with 4-hydroxycoumarins, leading to 3-(2-methoxymethoxymethyl)aryl-4-hydroxycoumarin derivatives in good to high yields. These compounds underwent a cascade sequence of reactions, deprotection-halogenation-annulation, to afford polyoxygenated tetracyclic 6H,11H-[2]benzopyrano-[4,3-c] [1]benzopyran-11-ones in good yields. Some compounds showed a moderate cytotoxicity against human epithelial mammary HBL100 cells.

The three-step one-pot α-arylation-annulation sequence leading to the reaction of 4-hydroxycoumarins with in situ generated 2-(bromomethyl)aryllead triacetates carried out in the presence of a combination of ortho-phenantroline-potassium tert-butoxide afforded tetracyclic benzo[b]pyran compounds in good to high yields.

Tris[ortho-chloromethylphenyl]bismuth diacetate reacted with phenols and enolisable substrates in the presence of a base to afford good yields of oxaphenanthrene derivatives.

Phenylbiphenyl-2,2′-ylenebismuth diacetate reacted with nucleophiles under basic conditions to give modest to good yields of the C-phenylated substrates. Under copper catalysis, it reacted with hydroxy or amino groups to give the products of O- or N-phenylation. In both sets of reaction conditions, this reagent showed a reduced reactivity compared to the analogous triphenylbismuth diacetate reagent. It showed also a high regioselectivity as only the phenyl derivatives were detected and isolated.