Evgeniya B. Logashenko

Synthesis and Pro-Apoptotic Activity of Novel Glycyrrhetinic Acid Derivatives

Triterpenoids are used for medicinal purposes in many countries. Some, such as oleanolic and glycyrrhetinic acids, are known to be anti‐inflammatory and anticarcinogenic. However, the biological activities of these naturally occurring molecules against their particular targets are weak, so the synthesis of new synthetic analogues with enhanced potency is needed. By combining modifications to both the A and C rings of 18βH‐glycyrrhetinic acid, the novel synthetic derivative methyl 2‐cyano‐3,12‐dioxo‐18βH‐olean‐9(11),1(2)‐dien‐30‐oate was obtained. This derivative displays high antiproliferative activity in cancer cells, including a cell line with a multidrug‐resistance phenotype. It causes cell death by inducing the intrinsic caspase‐dependent apoptotic pathway.

Synthesis of novel 2-cyano substituted glycyrrhetinic acid derivatives as inhibitors of cancer cells growth and NO production in LPS-activated J-774 cells

Here we report the synthesis and biological activity of new semi-synthetic derivatives of naturally occurring glycyrrhetinic acid bearing a 2-cyano-3-oxo-1-en moiety in the A-ring and double bonds and carbonyl groups in the C, D and E rings. Bioassays using murine macrophage-like and tumor cells show that compound 4, which differs from Soloxolone methyl by the absence of a 9(11)-double bond in the C-ring, displays anti-inflammatory and inhibitory activities with respect to tumor cells with a high selectivity index value.

Synthesis and biological activity of novel deoxycholic acid derivatives.

We report the synthesis and biological activity of new semi-synthetic derivatives of naturally occurring deoxycholic acid (DCA) bearing 2-cyano-3-oxo-1-ene, 3-oxo-1(2)-ene or 3-oxo-4(5)-ene moieties in ring A and 12-oxo or 12-oxo-9(11)-ene moieties in ring C. Bioassays using murine macrophage-like cells and tumour cells show that the presence of the 9(11)-double bond associated with the increased polarity of ring A or with isoxazole ring joined to ring A, improves the ability of the compounds to inhibit cancer cell growth.

Synthesis and Biological Activity of Novel Glycyrrhetic Acid Derivatives

Schemes for the treatment of different types of malignant tumors are based on the use of surgical methods combined with highdosage polychemother� apy. A serious flaw of the latter is the high toxicity of contemporary antitumor agents against vital organs and systems of organism. Associated side effects decrease the efficacy and in some cases limit the use of antitumor agents. The problem of residual tumor clone remains unsolved. Tumor cells that survive che� motherapy show drug resistance against a wide range of pharmaceuticals and often cause the recurrence of disease in an even more severe form. Therefore, the urgent task is to search for new antitumor agents that provide high treatment selectivity and efficacy. The use of substances obtained by synthetic trans� formations of plant metabolites, especially those that are known reliably to show biological activity and available at present or in future as a source of raw materials is an important tendency of medicinal chemistry intended for the development of new effi� cient antitumor agents. These types of compounds involve pentacyclic triterpenes whose wide spectrum of pharmacological activity attracts and expands the interest of researchers in these compounds (1-5).

5′-Norcarbocyclic analogues of furano[2,3-d]pyrimidine nucleosides

Abstract 5′-Norcarbocyclic analogues of furano[2,3-d]pyrimidine nucleosides as well as 5-bromo and 5-iodouracil derivatives were synthesized to evaluate their potential antitumor activity. The halogenated derivatives display no cytotoxicity with respect to all tested cells: KB-3-1 (human epidermoid carcinoma), HeLa (human cervical epithelioid carcinoma), HuTu-80 (human duodenal cancer), B16 (mouse melanoma), and MDCK (normal epithelial). The cytotoxicity of the non-halogenated furano[2,3-d]pyrimidine derivatives increases with the lengthening of the alkyl chain of the substituent from 45 to 60 μm for octyl to from 3 to 10 μm for dodecyl.

Novel derivatives of deoxycholic acid bearing aliphatic or cyclic diamine moieties at the C-3 position: Synthesis and evaluation of anti-proliferative activity

A new library of deoxycholic acid derivatives bearing nitrogen-containing moieties at the C-3 position was synthesised from epoxy derivative 1 via an epoxide ring-opening reaction promoted by aliphatic or cyclic diamines and fully characterised by NMR and mass-spectroscopy. The synthesised compounds were screened for cytotoxicity against four human tumour cell lines. The results showed that some of the novel diamine-bearing derivatives displayed improved anti-proliferative activities over the parent compound DCA. Among them, a 1-methylpiperazine containing compound (6) showed promising activity and the highest selectivity against tumour cells of enterohepatic origin (HepG2: IC50=3.6µM, SI=9.0; HuTu-80: IC50=4.6µM, SI=6.9) and was identified as a lead molecule.

Novel 5′-Norcarbocyclic Derivatives of Bicyclic Pyrrolo- and Furano[2,3-d]Pyrimidine Nucleosides

Here we report the synthesis and biological activity of new 5′-norcarbocyclic derivatives of bicyclic pyrrolo- and furano[2,3-d]pyrimidines with different substituents in the heterocyclic ring. Lead compound 3i, containing 6-pentylphenyl substituent, displays inhibitory activity with respect to a number of tumor cells with a moderate selectivity index value. Compound 3i induces cell death by the apoptosis pathway with the dissipation of mitochondrial potential.

Novel Glycyrrhetinic Acid Derivative Soloxolone Methyl Inhibits the Inflammatory Response and Tumor Growth in vivo

Due to wide spreading of inflammatory disease and imperfection of available anti-inflammatory drugs, mainly associated with their serious side effects, searching for new anti-inflammatory agents is a pressing problem. Natural triterpenoids and their synthetic analogs are a promising source of new drugs. In this study, we have investigated the anti-inflammatory and antitumor effects in vivo of the glycyrrhetinic acid derivative soloxolone methyl (SM), or methyl 2-cyano-3,12-dioxo-18βH-olean-9(11),1(2)-dien-30-oate. SM was shown to efficiently suppress the development of edema in a mouse model of carrageenan- or histamine- induced acute inflammation. SM also inhibited the tumor growth and reduced the tumor cell count in the ascitic fluid in mice bearing Krebs-2 carcinoma, the development of which is accompanied by an inflammatory process in the surrounding tissues.

Synthesis and evaluation of antitumor, anti-inflammatory and analgesic activity of novel deoxycholic acid derivatives bearing aryl- or hetarylsulfanyl moieties at the C-3 position

HIGHLIGHTSFormation of C‐3&bgr;‐epoxy derivatives of DCA with high stereoselectivity.Synthesis of new DCA derivatives via an epoxide ring opening reaction with S‐nucleophiles.Sensitivity of tumor cell lines to synthesised compounds was HuTu‐80 > KB‐3–1 > HepG2 > MH‐22a.Epoxide moiety at the C‐3 position was key for high anti‐proliferative and anti‐NO activities.All tested compounds exhibited bioactivity in different edema models. ABSTRACT Novel deoxycholic acid (DCA) derivatives were stereoselectively synthesised with –OH and –CH2SR moieties at the C‐3 position, where R was a substituted aryl [2‐aminophenyl (8) or 4‐chlorophenyl (9)] or hetaryl [1‐methylimidazolyl (5), 1,2,4‐triazolyl (6), 5‐amino‐1,3,4‐thiadiazolyl (7), pyridinyl (10) or pyrimidinyl (11)]. These compounds were prepared in good yields from the C‐3&bgr;‐epoxy derivative 2 in the epoxide ring‐opening reaction by S‐nucleophiles. These derivatives were evaluated for their in vitro anti‐proliferation activity in a panel of tumor cell lines. Data showed that: (i) heterocycle‐containing derivatives displayed higher cytotoxicity profiles than the parent molecule; (ii) heterocyclic substituents were more preferable than aryl moieties for enhancing anti‐proliferation activity; (iii) the sensitivity of tumor cell lines to analysed compounds decreased in the following order: HuTu‐80 (duodenal carcinoma) > KB‐3–1 (cervical carcinoma) > HepG2 (hepatocellular carcinoma) > MH‐22a (hepatoma); (iv) compounds 5, 6 and 11 exhibited a high cytotoxic selectivity index (HuTu‐80: SI > 7.7, 38.5 and 12.0, respectively). Compounds 2 and 6–8 markedly inhibited NO synthesis by interferon &ggr;‐induced macrophages. Screening for anti‐inflammatory activity of these derivatives in vivo showed their high potency on histamine‐ (5, 10) and formalin‐ (2, 10, 11) induced paw edema models.

Soloxolone methyl inhibits influenza virus replication and reduces virus-induced lung inflammation

Highly pathogenic influenza viruses pose a serious public health threat to humans. Although vaccines are available, new antivirals are needed to efficiently control disease progression and virus transmission due to the emergence of drug-resistant viral strains. In this study, we describe the anti-viral properties of Soloxolone methyl (SM) (methyl 2-cyano-3,12-dioxo-18βH-olean-9(11),1(2)-dien-30-oate, a chemical derivative of glycyrrhetinic acid) against the flu virus. Anti-flu efficacy studies revealed that SM exhibits antiviral activity against the H1N1 influenza A virus in a dose-dependent manner causing a more than 10-fold decrease in virus titer and a reduction in the expression of NP and M2 viral proteins. In a time-of-addition study, SM was found to act at an early stage of infection to exhibit an inhibitory effect on both the attachment step and virus uptake into cells. Also, in infected cells SM downregulates the expression of the inflammatory cytokines IL-6 and TNF-α. In infected mice, SM administered intranasally prior to and after infection significantly decreases virus titers in the lung and prevents post-challenge pneumonia. Together, these results suggest that Soloxolone methyl might serve as an effective therapeutic agent to manage influenza outbreaks and virus-associated complications, and further preclinical and clinical investigation may be warranted.