Ismail Hakki Akgun

Cytotoxic naphthoquinones from Alkanna cappadocica.

In a continuing program to discover new anticancer agents from plants, especially naphthoquinones from the Alkanna genus, Alkanna cappadocica was investigated. Bioassay-guided fractionation of a dichloromethane/methanol (1:1) extract of the roots led to the isolation of four new and four known naphthoquinones. The known compounds are 11-deoxyalkannin (1), beta,beta-dimethylacrylalkannin (2), 11-O-acetylalkannin (3), and alkannin (4). The new compounds 5-O-methyl-11-deoxyalkannin (5), 8-O-methyl-11-deoxyalkannin (6), 5-O-methyl-11-O-acetylalkannin (7), and 5-O-methyl-beta,beta-dimethylacrylalkannin (8) were characterized by spectroscopic analyses (LC-ESIMS, 1D and 2D NMR). Cytotoxicity of the isolated compounds was evaluated versus 12 human cancer cell lines, HT-29, MDA-MB-231, PC-3, AU565, Hep G2, LNCaP, MCF7, HeLa, SK-BR-3, DU 145, Saos-2, and Hep 3B together with two normal cell lines, VERO and 3T3, by using the MTT assay. Compound 7 showed remarkable cytotoxicity with IC(50) values between 0.09 and 14.07 muM. It was more potent than the other compounds in six out of 12 cancer cell lines and the positive controls doxorubicin and etoposide. The mono-O-methylated alkannin derivatives and their cytotoxicities are reported for the first time.

Induction of Gentiana cruciata hairy roots and their secondary metabolites

Gentiana cruciata L. (cross gentian) is a medicinal and ornamental plant. The root extracts of this species are known to exhibit many curative properties. The natural Gentiana populations are exposed to great danger because of their uncontrolled usage. In this study, hairy roots from Gentiana cruciata L. stem and leaf explants belonging to three different clones were induced by inoculation with four different Agrobacterium rhizogenes wild strains namely A4, 15834, 8196 and R1000. Induction of the root transformation was significantly dependent on the explant type used. On the other hand, the genotype and bacterial strain had no significant effect on hairy root formation. Hairy root formation percentages of the explants varied between 5.6–33.3% in the stem explants, and between 0.0–6.7% in the leaf explants. Transformations of the hairy roots were confirmed by PCR using rolC specific primers, and revealed the absence of contaminating A. rhizogenes with virC primers. Total of twelve hairy root clones were obtained, and their secondary metabolite content was also analyzed by HPLC. Quantitative results exhibited that gentiopicroside was the most abundant compound in all root samples. Furthermore, metabolites such as loganic acid, swertiamarin, and sweroside were also identified and quantified in the samples.

Cycloartane-type sapogenol derivatives inhibit NFκB activation as chemopreventive strategy for inflammation-induced prostate carcinogenesis

HIGHLIGHTS9,19‐cyclolanostane derivatives starting from cycloastragenol were synthesized.Five analogs were selected to be screened for their anti‐inflammatory properties.The compounds inhibited NF&kgr;B activation.They were shown to be promising anti‐inflammatory agents.The compounds are noteworthy candidates for prostate cancer chemoprevention. ABSTRACT Chronic inflammation is associated to 25% of cancer cases according to epidemiological data. Therefore, inhibition of inflammation‐induced carcinogenesis can be an efficient therapeutic approach for cancer chemoprevention in drug development studies. It is also determined that anti‐inflammatory drugs reduce cancer incidence. Cell culture‐based in vitro screening methods are used as a fast and efficient method to investigate the biological activities of the biomolecules. In addition, saponins are molecules that are isolated from natural sources and are known to have potential for tumor inhibition. Studies on the preparation of analogues of cycloartane‐type sapogenols (9,19‐cyclolanostanes) have so far been limited. Therefore we have decided to direct our efforts toward the exploration of new anti‐tumor agents prepared from cycloastragenol and its production artifact astragenol. The semi‐synthetic derivatives were prepared mainly by oxidation, condensation, alkylation, acylation, and elimination reactions. After preliminary studies, five sapogenol analogues, two of which were new compounds (2 and 3), were selected and screened for their inhibitory activity on cell viability and NF&kgr;B signaling pathway activity in LNCaP prostate cancer cells. We found that the astragenol derivatives 1 and 2 as well as cycloastragenol derivatives 3, 4, and 5 exhibited strong inhibitory activity on NF&kgr;B signaling leading the repression of NF&kgr;B transcriptional activation and suppressed cell proliferation. The results suggested that these molecules might have significant potential for chemoprevention of prostate carcinogenesis induced by inflammatory NF&kgr;B signaling pathway.

Identification Strategies for Bioactive Secondary Metabolites of Fungal Origin

In the present review article, we have described several fungi as a promising and evolving source of new and bioactive secondary metabolites for drug discovery processes. Also, the review has outlined isolation and identification strategies of known and novel fungal metabolites from endophytic fungi, fungi isolated from marine sources and extreme environments, etc. The chapter highlights how recent advances in biochemistry, genetics, analytical technologies and bioinformatics have significantly influenced the process of discovery of novel bioactive compounds in fungi. Combination of microfractionation, high-resolution mass spectroscopy and liquid chromatography with emerging technologies such as microfluidics has potential to augment the efficiency of identification procedures for novel bioactive molecules and become effective tools for bioengineers to adapt these microorganisms for industrial applications.