Conversion of antibacterial quinolone drug levofloxacin to potent cytotoxic agents.

Levofloxacin, the optical S-(-) isomer of ofloxacin, is a broad-spectrum antibacterial agent widely used to control various infections caused by Gram-positive and Gram-negative bacteria. While the COOH group is necessary for antibacterial activity, its modification can offer anticancer activity to the fluoroquinolone framework. Therefore, several levofloxacin carboxamides 11a-j and 12 containing 5-substituted-1,3,4-thiadiazole residue were synthesized and screened in vitro for their anticancer activity. The in vitro MTT viability assay revealed that the most compounds had significant activity against cancer cells MCF-7, A549, and SKOV3. In particular, the 3-chloro- and 4-fluoro- benzyl derivatives (11b and 11h), with IC50 values of 1.69-4.76 µM were as potent as or better than doxorubicin. It should be noted that the mother quinolone levofloxacin showed no activity on the tested cancer cell lines. The SAR analysis demonstrated that the 3-chloro or 4-fluoro substituent on the S-benzyl moiety had positive effect on the activity. Further in vitro evaluations of the most promising compounds 11b and 11h by flow cytometric analysis and comet test revealed the ability of compounds in the induction of apoptosis and blockage of the cell proliferation at the G1-phase by nuclear fragmentation and DNA degradation in cancer cells. The obtained results demonstrated that the alteration of 6-COOH functional group in the levofloxacin structure and conjugation with a proper heterocyclic pharmacophore is a good strategy to obtain new anticancer agents.

Application of kojic acid scaffold in the design of non-tyrosinase enzyme inhibitors.

Kojic acid (KA) is a hydroxypyranone natural metabolite mainly known as tyrosinase inhibitor. Currently, this compound is used as a whitening agent in cosmetics and as an anti-browning agent in food industry. Given the easy-manipulation in different positions of the KA molecule, many investigations have been carried out to find new tyrosinase inhibitors derived from KA. Beside anti-tyrosinase activity, many KA-based compounds have been designed for targeting other enzymes including human neutrophil elastase, catechol-O-methyltransferase, matrix metalloproteinases, monoamine oxidase, human lactate dehydrogenase, endonucleases, D-amino acid oxidase, and receptors such as histamine H3 and apelin (APJ) receptors. This review could help biochemists and medicinal chemists in designing diverse KA-derived enzyme inhibitors.

Synthesis and biological assessment of ciprofloxacin-derived 1,3,4-thiadiazoles as anticancer agents.

The quinolone-3-carboxylic acid scaffold is essential structure for antibacterial activity of fluoroquinolones such as ciprofloxacin. Modification of 3-carboxylic functionality in this structure can be used for switching its activity from antibacterial to anticancer. Accordingly, a series of C-3 modified ciprofloxacin derivatives containing N-(5-(benzylthio)-1,3,4-thiadiazol-2-yl)-carboxamide moiety was synthesized as novel anticancer agents. Most of compounds showed significant activity against MCF-7, A549 and SKOV-3 cancer cells in the MTT assay. In particular, compounds 13a-e and 13g were found to be as potent as standard drug doxorubicin against MCF-7 cell line (IC50s = 3.26-3.90 µM). Furthermore, the 4-fluorobenzyl derivatives 13h and 14b with IC50 values of 3.58 and 2.79 µM exhibited the highest activity against SKOV-3 and A549 cells, being as potent as doxorubicin. Two promising compounds 13e and 13g were further tested for their apoptosis inducing activity and cell cycle arrest. Both compounds could significantly induce apoptosis in MCF-7 cells, while compound 13e was more potent apoptosis inducer resulting in an 18-fold increase in the proportion of apoptotic cells at the IC50 concentration in MCF-7 cells. The cell cycle analysis revealed that compounds 13e and 13g could increase cell portions in the sub-G1 phase, inducing oligonucleosomal DNA fragmentation and apoptosis confirmed by comet assay.

Modification of 7-piperazinylquinolone antibacterials to promising anticancer lead compounds: Synthesis and in vitro studies.

Amongst the fluoroquinolone antibacterials, the 7-piperazinyl containing chemotypes such as norfloxacin, enoxacin, ciprofloxacin, pefloxacin, lomefloxacin, enrofloxacin, ofloxacin, levofloxacin, gatifloxacin and sparfloxacin have been shown to possess non-classical activities including cytotoxicity against different cancer cell lines, induction of apoptosis, and cell cycle arrest at the S/G2 stage. Additionally, piperazinylquinolones (PQs) have enough flexibility for chemical modification via their N-4 of piperazine ring and carboxylic acid at C-3. Therefore, PQs have been considered as a starting point for design and development of new anticancer agents. This review has focused on the recent synthetic modifications of PQs which led to N-substituted and/or C-3 modified PQs with potential anticancer activity.

The genus Hymenocrater: a comprehensive review.

CONTEXT: The genus Hymenocrater Fisch. et Mey. (Lamiaceae) contains over 21 species in the world. Some species have been used in folk medicine around the world. The present review comprises the ethnopharmacological, phytochemical and therapeutic potential of various species of Hymenocrater. OBJECTIVE: This review brings together most of the available scientific research regarding the genus Hymenocrater. Through this review, the authors hope to attract the attention of natural product researchers throughout the world to focus on the unexplored potential of Hymenocrater species. METHODS: This review has been compiled using references from major databases such as Chemical Abstracts, Medicinal and Aromatic Plants Abstracts, ScienceDirect, SciFinder, Google Scholar, Scopus, PubMed, Springer Link and books, without limiting the dates of publication. General web searches were also carried out using Google and Yahoo search engines by applying some related search terms (e.g., Hymenocrater spp., phytochemical, pharmacological, extract, essential oil and traditional uses). The articles related to agriculture, ecology, and synthetic works and those using languages other than English or Persian have been excluded. RESULTS: The genus Hymenocrater contains essential oil. Flavonoids, phenolic acids and terpenoids are important constituents of this genus. The pharmacological studies confirmed that the species of the genus Hymenocrater showed antimicrobial, antiparasitic, antioxidant, anticancer and antidiabetic activities. CONCLUSION: This review discusses the current knowledge of Hymenocrater species that review therapeutic potential, especially their effects on the cancer cells and gaps offering opportunities for future research.