Photodegradation of Bexarotene and Its Implication for Cytotoxicity.

A detailed understanding of the stability of an active pharmaceutical ingredient and a pharmaceutical dosage form is essential for the drug-development process and for safe and effective use of medicines. Photostability testing as an inherent part of stability studies provides valuable knowledge on degradation pathways and structures of products generated under UV irradiation. Photostability is particularly important for topically administered drugs, as they are more exposed to UV radiation. Bexarotene is a more recent third-generation retinoid approved by the U.S. Food and Drug Administration and the European Medicines Agency as a topically applied anticancer agent. The present study aimed to assess bexarotene photostability, including the presence of UV filters, which have been permitted to be used in cosmetic products in Europe and the USA. The bexarotene photostability testing was performed in ethanol solutions and in formulations applied on PMMA plates. The UPLC-MS/MS technique was used to determine the tested substance. The presence of photocatalysts such as TiO2 or ZnO, as well as the organic UV filters avobenzone, benzophenone-3, meradimate, and homosalate, could contribute to degradation of bexarotene under UV irradiation. Four photocatalytic degradation products of bexarotene were identified for the first time. The antiproliferative properties of the degradation products of bexarotene were assessed by MTT assay on a panel of human adherent cancer cells, and concentration-dependent growth inhibition was evidenced on all tested cell lines. The cytotoxicity of the formed products after 4 h of UV irradiation was significantly higher than that of the parent compound (p < 0.05). Furthermore non-cancerous murine fibroblasts exhibited marked concentration-dependent inhibition by bexarotene, while the degradation products elicited more pronounced antiproliferative action only at the highest applied concentration.

Photostability Testing of a Third-Generation Retinoid-Tazarotene in the Presence of UV Absorbers.

Exposure of a drug to UV irradiation could affect its physicochemical properties. Hence, photostability testing is essential for topically administered drugs. Tazarotene, a receptor-selective, third-generation retinoid, is commonly used to treat acne vulgaris and psoriasis. In the present study, an in-depth analysis of the photostability of tazarotene in ethanolic solution in the presence of zinc oxide and/or titanium dioxide as well as benzophenone-type UV filters was performed. Eleven presumed products were derived from the photocatalytic degradation of tazarotene using ultra-performance liquid chromatography-tandem mass spectrometry, and transformation pathways were proposed. The degradation process mainly affected the 4,4-dimethyl-3,4-dihydro-2H-thiopyran moiety. The fragments most susceptible to oxidation were the methyl groups and the sulfur atom. Moreover, in the presence of sulisobenzone, under UV irradiation, tazarotene was subjected to a degradation process, which resulted in two photodecomposition products. In silico studies performed by OSIRIS Property Explorer demonstrated that five of the degradation products could be harmful in terms of the reproductive effects, which are associated with 3,4-dihydro-6-methyl-2H-1-benzothiopyran 1,1-dioxide, while one of them demonstrated potential irritant activity. The cytotoxic properties of the degradation products of tazarotene were assessed by MTT assay on a panel of human adherent cancer cells. Time- and concentration-dependent growth inhibition was evidenced in ovary (A2780) and breast (MDA-MB-231) cancer cell lines. The potential implication of the outcomes of the present research requires further studies mainly concerning the photostability of tazarotene in the topical formulations.

Synthesis and Transformation of (-)-Isopulegol-Based Chiral ß-Aminolactones and ß-Aminoamides.

A library of isopulegol-based ß-amino acid derivatives has been developed from commercially-available (-)-isopulegol. Michael addition of primary and secondary amines towards α,ß-unsaturated γ-lactones was accomplished resulting in ß-aminolactones in highly-stereoselective reactions. Ring-opening of ß-aminolactones with different amines furnished excellent yields of ß-aminoamides. Moreover, the applicability of aminolactones in peptide synthesis was examined by opening the lactone ring with α- and ß-aminoesters, providing dipeptides as promising chiral substrates for the synthesis of foldamers. The antiproliferative activities of ß-aminolactones and ß-aminoamides were explored, and the structure-activity relationships were studied from the aspects of the stereochemistry of the monoterpene ring and the substituent effects on the ß-aminoamide ring system. The N-unsubstituted (-)-isopulegol-based ß-aminoamides exhibited considerable antiproliferative activity against a panel of human adherent cancer cell lines (HeLa, MCF7 and MDA-MB-231).

New iridoids from the roots of Valeriana dioscoridis Sm.

Four new iridoids (1-4), together with three known iridoids (5-7), one known flavonoid glycoside, three phenolic acids and one phytosterol were isolated from the roots of Valeriana dioscoridis. Their structures were elucidated by means of NMR spectroscopy and mass spectrometry. This is the first report on the phytochemical composition of the non-volatile constituents of V. dioscoridis and the occurrence of a bis-iridoid glycoside in the genus Valeriana. The antiproliferative effects of the iridoids (1-7) were evaluated against three human cancer cell lines of gynacological origin (HeLa, A2780 and T47D) at 10, 30 and 60 µM concentrations, using the MTT assay and they elicited modest antiproliferative activity when compared to the reference agent, cisplatin.

Antiproliferative and Antimicrobial Activities of Selected Bryophytes.

One-hundred and sixty-eight aqueous and organic extracts of 42 selected bryophyte species were screened in vitro for antiproliferative activity on a panel of human gynecological cancer cell lines containing HeLa (cervix epithelial adenocarcinoma), A2780 (ovarian carcinoma), and T47D (invasive ductal breast carcinoma) cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and for antibacterial activity on 11 strains using the disc-diffusion method. A total of 99 extracts derived from 41 species exerted ≥25% inhibition of proliferation of at least one of the cancer cell lines at 10 µg/mL. In the cases of Brachythecium rutabulum, Encalypta streptocarpa, Climacium dendroides, Neckera besseri, Pleurozium schreberi, and Pseudoleskeella nervosa, more than one extract was active in the antiproliferative assay, whereas the highest activity was observed in the case of Paraleucobryum longifolium. From the tested families, Brachytheciaceae and Amblystegiaceae provided the highest number of antiproliferative extracts. Only 19 samples of 15 taxa showed moderate antibacterial activity, including the most active Plagiomnium cuspidatum, being active on 8 tested strains. Methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus aureus were the most susceptible to the assayed species. This is the first report on the bioactivities of these 14 species.

Stereoselective Synthesis, Synthetic and Pharmacological Application of Monoterpene-Based 1,2,4- and 1,3,4-Oxadiazoles.

Stereoselective synthesis of monoterpene-based 1,2,4- and 1,3,4-oxadiazole derivatives was accomplished starting from α,ß-unsaturated carboxylic acids, obtained by the oxidation of (-)-2-carene-3-aldehyde and commercially available (-)-myrtenal. 1,2,4-Oxadiazoles were prepared in two steps via the corresponding O-acylamidoxime intermediates, which then underwent cyclisation induced by tetrabutylammonium fluoride (TBAF) under mild reaction conditions. Stereoselective dihydroxylation in highly stereospecific reactions with the OsO4/NMO (N-methylmorpholine N-oxide) system produced α,ß-dihydroxy 1,2,4-oxadiazoles. Pinane-based 1,3,4-oxadiazoles were obtained similarly from acids by coupling with acyl hydrazines followed by POCl3-mediated dehydrative ring closure. In the case of the arane counterpart, the rearrangement of the constrained carane system occurred with the loss of chirality under the same conditions. Stereoselective dihydroxylation with OsO4/NMO produced α,ß-dihydroxy 1,3,4-oxadiazoles. The prepared diols were applied as chiral catalysts in the enantioselective addition of diethylzinc to aldehydes. All compounds were screened in vitro for their antiproliferative effects against four malignant human adherent cell lines by means of the MTT assay with the O-acylated amidoxime intermediates exerting remarkable antiproliferative action.

Gymnopeptides A and B, Cyclic Octadecapeptides from the Mushroom Gymnopus fusipes.

Mycochemical study of the mushroom Gymnopus fusipes led to the discovery of two new cyclopeptides. The two compounds, named as gymnopeptides A and B, are unprecedented highly N-methylated cyclic octadecapeptides. Detailed spectroscopic studies, Marfey's analysis, and a preliminary molecular modeling study suggested that both are natural cyclic ß hairpins. The isolated compounds exhibited striking antiproliferative activity on several human cancer cell lines, with nanomolar IC50 values.