Synthesis of C17-[5-methyl-1,3]-oxazoles by N-propargylation of triterpenic acids and evaluation of their cytotoxic activity.

A series of unexpected triterpenic C17-[5-methyl-1,3]-oxazoles along with targeted N-propargylamides was synthesized by an interaction of acid chlorides with propargylamine hydrochloride. We proposed that the formation of methyl oxazole passes through an alternative pathway by the participation of the terminal alkyne carbon atom and acid chloride intermediate with following intramolecular rearrangements. The synthesized compounds were evaluated for their cytotoxicity at the U.S. National Cancer Institute. 28-Nor-17-(5-methyloxazol-2-yl)-2-cyano-2,4-seco-3-nor-lup-4(23),20(29)-diene has demonstrated the highest activity with GI50 ranged from 1.03 to 16.4 µM against different cancer cell lines. Molecular docking in Kelch domain of Keap1 protein was performed to study a possible molecular target. Thus, we have shown for the first time that triterpenic C17-[5-methyl-1,3]-oxazoles are alternative products of the interaction of triterpenic acid chlorides with propargylamine hydrochloride and they have an advantage over corresponding N-propargylamides as cytotoxic agents.

[Synthesis and Anticancer Activity of Betulonic Acid Imidazolides].

Synthesis of lupane C28-imidazolides, contained 3-oxo-, 3-oximino- and 2-cyano-2,3-seco-4(23)-en-frag ments in cycle A was carried out. The most antitumor activity at. in vitro testing showed 3-oximino-lup- 20(29)-en-28-yl-1H-imidazole-1-carboxylate; which inhibited the growth or induced apoptosis of non-small lung cancer, colon cancer, breast cancer, CNS cancer, ovarian cancer, prostate cancer, leucosis, melanoma cells. In experiments in mice its moderate antitumor activity against grafted breast adenocarcinoma Ca 755 and adenocarcinima of colon was observed.

[Synthesis and cytotoxicity of triterpenoid seven members cyclic amines].

Synthesis of 3-deoxy-3a-homo-3a-aza-derivatives of betulin and erythrodiol from betulonic and oleanonic acids was carried out. The most antineoplastic activity with a wide range of action at in vitro testing showed 3-deoxy-3a-homo-3a-aza-28-hydroxy-12(13)-oleanene, which by results of profound studying could be recommended for in vivo investigation. Its modification in the C28 position by introduction of amethoxycinnamoyl fragment led to a loss of antineoplastic activity. 3-Deoxy-3a-homo-3a-aza-derivatives of betulin (3-(aminopropyl)-, 28-(2-carboxyethyl)carboxy-, and 28-cinnamoyloxy-) showed moderate antineoplastic activity in the case of Colon Cancer, Breast Cancer and Leukemia cell lines.

[Synthesis and cytotoxicity of allobetulin derivatives].

The synthesis and screening of antitumor activity in vitro (cytotoxicity) of various oxygen, nitrogen, sulfur and platinum-containing derivatives of allobetulin, including different arrangements of the double bonds in the A and B rings, penta- and hexacyclic ring A, 21-acetyl-20,28-epoxy-18α,19ßH-ursane-isomeric cycle E, was carry out. (3R,5R)-19ß,28-Epoxy-4,5-seco-18α-olean-3(5)-ozonide and 2,3-indolo-21ß-acetyl-20ß,28-epoxy-18α, H-19ß-ursane showed significant cytotoxic activity against melanoma MeWo and Leukemia SR cells, appropriately. (3S,5S)-Diastereomer of the first compound showed no cytotoxicity.

[Synthesis, structure and farmacologycal activity of (7R,8S)-epoxy-(13R,17R)-trioxolaneabietic acid].

The synthesis and X-ray diffraction established the structure of (7R,8S)-(see text for symbol)-(13R,17R)-trioxolaneabietic acid. Predicted by the computer system PASS antineoplastic activity and the ability to induce apoptosis, a mechanism of cell death, is correlated with experimentally shown cytotoxic activity against malignant cell line MeWo. Results of tests on animals have shown that abietic acid and its 9R,11S-epoxy-12R,15R-trioxolane derivative have anti-inflammatory and antiulcer activity in the absence of adverse effects on animal organisms.

[Synthesis of aminopropylaminoderivatives of betulinic and oleanolic acids].

On the basis of betulinic and oleanolic acids triterpenoids with different with different amine fragments: (3-aminopropoxy)-, 3-acetyl-(3-aminopropyl)amino-, 6-[bis(3-aminopropyl)amino]hexylamino-, (3-aminopropyl)-4-aminosulfonyl-4-phenylamino- at positions C3 and C28 were synthesized. It is shown that betulonic acid amide with 4,4'-diaminodiphenylsulfonic substituent don't render antitumor effect in mice with transplantable Lewis lung carcinoma, but possess significant anti-inflammatory activity.

[Synthesis and antitumor activity of betulin, erythrodiol and uvaol aminopropoxy derivatives].

The synthesis of aminopropoxy derivatives of betulin, erythrodiol, uvaol and oleantriol via cyanoethylation of triterpenoids hydroxyl groups and subsequent reduction of cyanoethyl fragments is described. High and specific in vitro antitumor activity (cytotoxicity) of 3beta,28-di-O-[3-(aminopropoxy)]lupa-20(29)-ene and 3beta-O-hydroxy-28-O-[3-(aminopropoxy)]olean-12-ene towards a wide range of human tumor cell lines is discovered. The aminopropoxy group is shown to be a new perspective pharmacophor group for design of anticancer agents on the basis of triterpenoids.

[Structural and functional characteristics of betulin derivatives].

The effect of betulin derivatives on persistence properties of microorganisms was studied in vitro. It was shown that the antipersistence action of the betulin derivatives depended on their structure and the microbial species. The experimental data on the structure - function relation could be useful in development and synthesis of new agents for therapy of chronic infections associated with persistence of bacterial pathogens in macroorganism.

[Synthesis of A-secomethylenamino- and substituted amidoximotriterpenoids].

Development of the functionalization of triterpenoids to A-secoamidoximes, A-secomethylenamines and branched 3-(3-aminopropylamino)-3-(3-aminopropoxy)amidoximes is illustrated by the betulonic acid ketoxime. An effective way to get of the derivatives of 20,29-dihydrolupanes using diborane is suggested. The antiviral and anti-tuberculosis activity data of some compounds are presented.

[Synthesis of new olean-18(19)-ene derivatives from allobetulin].

Effective synthesis of new olean-18(19)-ene triterpenoids based on interaction of allobetulin or its acetate with phosphorous oxychloride in pyridine under reflux is described. The structures of the synthesized 17-chloromethyl-oleane-18(19)-enes have been established with the help of NMR-spectroscopy and X-Ray analysis.

[Synthesis, modifications, and antimicrobial activity of the methylpiperazinyl amides of triterpenic acids].

N-Methylpiperazinyl amides of betulinic, platanic, glycyrrhetic, oleanolic, ursolic, and moronic acids were synthesized and modified. Betulin and betulonic acid showed antimicrobial activity against Staphylococcus aureus at a concentration of 90 mg/ml, and betulin manifested a bacteriostatic effect against Klebsiella pneumoniae at a concentration of 60 mg/ml. Among the studied N-methylpiperazinyl amides, the highest activity against S. aureus was observed for a betulonic acid derivative.

[Synthesis and anti-inflammatory activity of quinopimaric acid derivatives].

Under the action of PCl(5), the Beckman rearrangement of a 3 : 1 mixture of Z- and E-ketoximes of 18beta-hydroxydihydroquinopimaric acid resulted in 5'-caprolactam and isomeric caprolactams containing fragments of cyclic ether. Z- and E-ketoximes were separated as acetates. Using a carrageenan inflammation model, we demonstrated that the anti-inflammatory activity of quinopimaric acid derivatives was comparable with that of diclofenac.

[A one-step approach to the synthesis of germanicane triterpenoids from allobetulin].

A new triterpenoid of the germanicane series 3S,19R-diacetoxy-17-iodomethylenoleanane has been synthesized by treating allobetulin with acetyl chloride and sodium iodide in acetonitrile. The structure of the compound obtained has been corroborated by X-ray analysis data.

[Synthesis and pharmacological activity of amides and ozonolysis product of maleopimaric acid].

The synthesis of a new group of maleopimaric acid amides containing fragments of the methyl esters of amino acids, aliphatic amines, imidazole and N-methylpiperazine was carried out. Ozonolysis of methyl maleopimarate flows through the cleavage of double bond C18(19) and the disclosure of anhydrous cycle with formation of secotriacid. As a result of screening of anti-inflammatory and antiulcer activity of maleopimaric acid derivatives new effective compounds such as methyl esters of maleopimaric acid and product of ozonolysis - diterpenic secotriacid, maleopimaric acid amide with L-leucine were revealed. An important advantage of the compounds studied is the low toxicity and the presence of bidirectional activity in the absence of adverse effects on the animal.

[Synthesis of triterpenoid acylates - an effective reproduction inhibitors of influenza A (H1N1) and papilloma viruses].

The synthesis of a new group of triterpenoid acylates on the basis of oleanolic, glycyrrhetic and ursolic acids and betulin is described. In studying the activity of the synthesized compounds in relation to reproduction of virus pathogens of respiratory infections 28-O-methoxycynnamoylbetulin shows high activity against influenza type A (H1N1) the selectivity index SI > 100. The high activity of 3,28-dinicotinoylbetulin against papilloma virus (strain HPV-11) was detected, the selectivity index SI was 35.

Synthesis of triterpenoid acylates: Effective reproduction inhibitors of influenza A (H1N1) and papilloma viruses.

The synthesis of a new group of triterpenoid acylates has been conducted on the basis of oleanolic, glycyrrhetic, and ursolic acids and betulin. 28-ortho-Methoxycynnamoylbetulin has been demonstrated to possess high activity against the influenza type A (H1N1) virus with the selectivity index SI > 100 while studying the activity of the synthesized compounds in relation to the reproduction of viral pathogens of respiratory infections. The high activity of 3,28-dinicotinoylbetulin against the papilloma virus (strain HPV-11) was detected with the selectivity index SI 35.

[Synthesis and modification of triterpenoids with two lupan backbones].

The first derivatives containing two lupan backbones were synthesized by the interaction of betulonic acid chloride with diols (ethylene glycol and diethylene glycol) and monoethanolamine. A modification of ring A of ethylene-l,2-bis(betulonnate) led to its bis(3beta-aminopropyloxy) and bis(3,4-seco-2-cyano) derivatives.