New 1Z,5Z-diene macrodiolides: Catalytic synthesis, anticancer activity, induction of mitochondrial apoptosis, and effect on the cell cycle.

An original scheme was developed for the synthesis of previously undescribed unsaturated macrodiolides containing a 1Z,5Z-diene moiety in 44-80% yields and with high stereoselectivity (>95%) based on the intermolecular esterification of α,ω-diols with α,ω-alka-nZ,(n + 4)Z-dienedicarboxylic acids (1,12-dodeca-4Z,8Z-dienedicarboxylic acid, 1,14-tetradeca-5Z,9Z-dienedicarboxylic acid, 1,18-octadeca-7Z,11Z-dienedicarboxylic acid) catalyzed by hafnium triflate [Hf(OTf)4]. The unsaturated dicarboxylic acids were prepared via homo-cyclomagnesiation of tetrahydropyran ethers of O-containing 1,2-dienes with EtMgBr in the presence of Mg metal and the Cp2TiCl2 catalyst (10 mol.%) and the subsequent Jones oxidation of pyran ethers formed after the acid hydrolysis of magnesacyclopentanes. The thus prepared macrodiolides exhibit high cytotoxic activity in vitro against Jurkat, K562, U937, Hek293 and HeLa cancer cell lines. It was found that induction of the programmed cell death in Jurkat cells by macrodiolides corresponds to the mitochondrial apoptosis pathway. Also, it was shown that the prepared macrodiolides efficiently suppress phosphorylation of Akt and p38 kinases and CREB transcription factor in cancer cells.

Diversity-oriented synthesis of spirothiazolidinediones and their biological evaluation.

We report a new synthetic approach to assemble spirothiazolidinediones via a [2 + 2 + 2] cyclotrimerization reaction and the derivatives were further functionalized through DA chemistry and click reaction. Using flow cytometry, it was shown for the first time that the new benzyl alcohol derivatives of thiazolidine-2,4-dione generated here are efficient apoptosis inducers in the HeLa, Hek293, U937, Jurkat, and K562 cell lines.

The first total synthesis of the marine acetylenic alcohol, lembehyne B - a selective inducer of early apoptosis in leukemia cancer cells.

The communication reports a new stereoselective method for the synthesis of a natural acetylenic alcohol, lembehyne B. The key stage of the process uses new cross-cyclomagnesiation reaction of aliphatic and oxygenated 1,2-dienes with Grignard reagents in the presence of a catalytic amount of Cp2TiCl2. A study of the cytotoxic properties of lembehyne B on tumor cell lines using flow cytometry demonstrated that this is a selective inducer of early apoptosis of the Jurkat, HL-60 and K562 cell cultures and hypodiploid (sub-G1) sub-population inducer in cell cycle studies for all cell lines used.

Short Route to the Total Synthesis of Natural Muricadienin and Investigation of Its Cytotoxic Properties.

An original synthesis of the acetogenin muricadienin, the bioprecursor of solamin, has been developed. The key step in the five-step 41% overall yield synthesis is the catalytic cross-cyclomagnesiation reaction of functionally substituted 1,2-dienes with EtMgBr in the presence of Cp2TiCl2 and magnesium metal. It has been demonstrated for the first time that muricadienin exhibits a moderate in vitro inhibitory activity against topoisomerases I and IIα, key cell cycle enzymes. Using flow cytometry, muricadienin was shown to have high cytotoxicity toward the HEK293 kidney cancer cells (IC50 0.39 µM).

New 1,3-Diynoic Derivatives of Natural Lembehyne B: Stereoselective Synthesis, Anticancer, and Neuritogenic Activity.

An original method has been developed for the synthesis of 1,3-dyine derivatives of natural lembehyne B in high yields (50-67%) and with high selectivity (>98%). The key stage of the synthesis is new Ti-catalyzed cross-cyclomagnesiation of oxygenated and aliphatic 1,2-dienes induced by Grignard reagents. For studying the effect of the structure on the antitumor and neuritogenic activities, a series of lembehyne B analogues with different distances between the terminal hydroxy group and the 1,3-diyne moiety was prepared and tested for neuritogenic activity on mouse neuroblastoma Neuro 2A cells and for cytotoxicity, induction of apoptosis, and effects on the cell cycle using Jurkat, U937, K562, HeLa, and Hek293 tumor cell lines.

Synthesis of C60 Fullerene-Quadricyclane Hybrid Compound and Its Preliminary In Vitro Antitumor Activity in Combination with Cisplatin.

This paper describes the authors' preliminary studies directed toward the possibility of the practical implementation of the idea to design efficient antitumor drugs based on hybrid molecules composed of fullerene C60 and quadricyclanes. The essence of the proposed idea is that these hybrid molecules are able to cleave DNA owing to the fullerene moiety they contain and to simultaneously thermally affect tumor cells via cleavage of the carbon-carbon bond in quadricyclanes under the action of Pd and Pt ions. As a result, testing of the cytotoxic activity in vitro for a number of fullerene C60 hybrids with the norbornadiene or quadricyclane moieties against the human T-lymphoblastic leukemia cells (Jurkat cells) in combination of the known cisplatin drug, which was taken as the source of Pt ions, showed a statistically reliable dose-dependent increase in the number of dead cells in each group, which were formed according to the amount of cisplatin added, in comparison with the control, that is, cells treated with cisplatin or quadricyclane fullerene derivatives alone. Indeed, the difference between the percentages of viable cells after treatment with either cisplatin alone or cisplatin in combination with methanofullerene 5 ranged from ∼10% (for Pt (0.015 mkM), 5 (0.015 mkM)) to ∼55% (for Pt (0.03 mkM), 5 (0.045 mkM)).

Synthesis of New Dihydroquinopimaric Acid Analogs with Nitrile Groups as Apoptosis-Inducing Anticancer Agents.

BACKGROUND: Cyan-containing compounds are of great interest as potential anticancer agents. Terpenoids can severe as a natural matrix for the development of promising derivatives with antitumor activity. METHODS: The 2-cyanoethoxy methyl dihydroquinopimarate derivatives (5-9) were synthesized by the reaction of the intermediates (1-4) with acrylonitrile in the presence of alkali (30% KOH solution) using triethylbenzylammonium chloride. The cytotoxicity evaluation was carried out according to the National Cancer Institute (NCI) Protocol, while apoptosis was studied by flow cytometric analysis of Annexin V and 7-aminoactinomycin D staining and cell cycle was analyzed using the method of propidium iodide staining. RESULTS: Synthesis of new dihydroquinopimaric acid derivatives with nitrile groups was carried out. The obtained cyanoethyl derivatives were converted into tetrazole, amine, oxadiazole and amidoxime analogs. The primary screening for antitumor activity showed the highest cytotoxic potency of the cyanoethyl-substituted compounds. The introduction of cyanoethyl groups at C-1, C-4 and C-1, C-4, C-20 positions of dihydroquinopimaric acid methyl ester provided antiproliferative effect towards the Jurkat, K562, U937, and HeLa tumor cell cultures (CC50=0.045-0.154µM). These nitrile derivatives are effective inducers of tumor cell apoptosis affecting the S and G2 phases of the cell cycle in a dose-dependent manner. CONCLUSION: The cyanoethyl analogs of dihydroquinopimaric acid reported herein are apoptosis inducers and cytotoxic agents. These findings will be useful for the further design of more potent cytotoxic agents based on natural terpenes.

Catalytic cyclometallation in steroid chemistry V: Synthesis of hybrid molecules based on steroid oximes and (5Z,9Z)-tetradeca-5,9-dienedioic acid as potential anticancer agents.

Synthetic analogues of natural 5Z,9Z-dienoic acids - hybrid molecules based on the oximes of cholesterol, pregnenolone, and androsterone with 1,14-tetradeca-5Z,9Z-dienedicarboxylic acid - were synthesized for the first time and studied for antitumor activity in vitro. The acid was prepared using catalytic cyclomagnesiation of O-containing 1,2-dienes with Grignard reagent in the presence of Cp2TiCl2 as the key step. Using flow cytometry, it was shown for the first time that the new molecules are efficient apoptosis inducers in the HeLa, Hek293, U937, Jurkat, and K562.

Catalytic cyclometallation in steroid chemistry VI: Targeted synthesis of hybrid molecules based on steroids and tetradeca-5Z,9Z-diene-1,14-dicarboxylic acid and study of their antitumor activity.

Hybrid molecules based on a number of steroids (cholesterol, pregnenolone, androsterone) and 1,14-tetradeca-5Z,9Z-dienedicarboxylic acid linked via mono- and diethylene glycol spacers were synthesized for the first time and studied for antitumor activity in vitro. The acid was prepared using catalytic cyclomagnesiation of oxygenated 1,2-dienes with Grignard reagent in the presence of Cp2TiCl2 as the key synthetic step. Using flow cytometry, the new molecules were shown for the first time to be efficient apoptosis inducers in the HeLa, Hek293, U937, Jurkat, and K562 cell cultures and to have dose-dependent effect on the S and G2 phases of the cell cycle.

Novel Hybrid Molecules on the Basis of Steroids and (5Z,9Z)-Tetradeca-5,9-dienoic Acid: Synthesis, Anti-Cancer Studies and Human Topoisomerase I Inhibitory Activity.

Novel steroid derivatives of 5Z,9Z-dienoic acids were prepared by the DCC/DMAP-catalyzed esterification of (5Z,9Z)-tetradeca-5,9-dienoic acid with hydroxy steroids. High cytotoxicity towards the HEK293, Jurkat, K562 cancer cell lines and human topoisomerase I (hTop1) inhibitory activity in vitro were found for the synthesized acids. A probable mechanism of topoisomerase I inhibition was hypothesized on the basis of in silico studies resorting to docking.