Koichi Takeya

Bioactive Cyclic Peptides from Higher Plants

Cyclic peptides comprise a class of naturally occurring molecules, which exhibit a range of biological activities, and have attracted great interest from a biogenetic point of view as well as providing challenging targets for total synthesis. This review covered the structure elucidation and biological activity of cyclic peptides recently isolated from higher plants such as Amaranthaceae, Annonaceae, Caryophyllaceae, Compositae, Linaceae, Rutaceae, and Rubiaceae.

Isolation, Structure Determination, and Synthesis of Allo‐RA‐V and Neo‐RA‐V, RA‐Series Bicyclic Peptides from Rubia cordifolia L.

Two bicyclic hexapeptides, allo-RA-V (4) and neo-RA-V (5), and one cyclic hexapeptide, O-seco-RA-V (6), were isolated from the roots of Rubia cordifoliau2005L. Their gross structures were elucidated on the basis of spectroscopic analysis and X-ray crystallography of compound 5. The absolute stereochemistry of compounds 4 and 5 were established by their total syntheses, and the absolute stereochemistry of compound 6 by chemical correlation with deoxybouvardin (3). Comparison of the 3D structures of highly active RA-VII (1) with less-active compounds 4 and 5 suggests that the orientation of the Tyr-5 and/or Tyr-6 phenyl rings plays a significant role in their biological activity. The isolation of peptides 4-6, along with compound 3, and the comparison of their structures seem to indicate that peptide 6 may be the common precursor to bicyclic peptides 3-5 in the plant.

Fluorination of triptolide and its analogues and their cytotoxicity.

The reaction of triptolide and its analogues with a fluorinating agent, that is, bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) or (diethylamino)sulfur trifluoride (DAST), was studied. One of the fluorinated products, 14beta-dehydroxy-14beta-fluoro triptolide, was found to be more cytotoxic than the parent natural triptolide.

The current status of tailor-made medicine with molecular biomarkers for patients with clear cell renal cell carcinoma

AbstractAppropriate use of multiple reliable molecular biomarkers in the right context will play a role in tailor-made medicine of clear cell renal cell carcinoma (RCC) patients in the future. A total of 11,056 patients from 53 studies were included in this review. The article numbers of the each evidence levels, using the grading system defined by the Oxford Centre for Evidence-based Medicine, in 1b, 2a, 2b, and 3b were 5 (9xa0%), 18 (34xa0%), 29 (55xa0%), and 1 (2xa0%), respectively. The main goal of using biomarkers is to refine predictions of tumor progression, pharmacotherapy responsiveness, and cancer-specific and/or overall survival. Currently, carbonic anhydrase (CA9) and vascular endothelial growth factor (VEGF) in peripheral blood and p53 in tumor tissues are measured to predict metastasis, while VEGF-related proteins in peripheral blood are used to assess pharmacotherapy responsiveness with sunitinib. Furthermore, interleukin 8, osteopontin, hepatocyte growth factor, and tissue inhibitors of metalloproteinases-1 in peripheral blood enable assessment of responsiveness to pazopanib treatment. Other reliable molecular biomarkers include von Hippel–Lindau gene alteration, hypoxia-inducible factor-1α, CA9, and survivin in tumor tissues and VEGF in peripheral blood for predicting cancer-specific survival. In the future, studies should undergo external validation for developing tailored management of clear cell RCC with molecular biomarkers, since individual institutional studies lack the generalization and consistency required to maintain accuracy among different patient series.n

Antitumor agents. 282. 2′-(R)-O-acetylglaucarubinone, a quassinoid from Odyendyea gabonensis as a potential anti-breast and anti-ovarian cancer agent.

A new quassinoid, designated 2-(R)-O-acetylglaucarubinone (1), and seven known quassinoids (2-8) were isolated, using bioactivity-guided separation, from the bark of Odyendyea gabonensis (Pierre) Engler [syn. Quassia gabonensis Pierre]. The structure of 1 was determined by spectroscopic analysis and by semisynthesis from glaucarubolone. Complete (1)H and (13)C NMR assignments of compounds 1-8 were also established from detailed analysis of two-dimensional NMR spectra, and the reported configurations in odyendene (7) and odyendane (8) were corrected. Compound 1 showed potent cytotoxicity against multiple cancer cell lines. Further investigation using various types of breast and ovarian cancer cell lines suggested that 1 does not target the estrogen receptor or progesterone receptor. When tested against mammary epithelial proliferation in vivo using a Brca1/p53-deficient mice model, 1 also caused significant reduction in mammary duct branching.

Differential conformational behaviors of α-mycolic acids in Langmuir monolayers and computer simulations

Phase diagrams of Langmuir monolayers of alpha-mycolic acids (alpha-MAs) from representative slow growing mycobacteria were intensively analyzed over a range of temperatures, by using so-called type-1 alpha-MAs having two cis-cyclopropyl groups from Mycobacterium tuberculosis, Mycobacterium kansasii and Mycobacterium avium-intracellulare complex (MAC) and type-3 alpha-MA, having one cis-cyclopropyl and one cis-double bond from Mycobacterium bovis BCG and MAC. Their intrachain groups are either cis-cyclopropyl or cis-double bond but the methylene chain segment lengths vary greatly. However, their monolayer features were alike: at lower temperatures and surface pressures, the molecules seemed to be in folded conformations, requiring larger mean molecular areas, whereas at higher temperatures and surface pressures, to be in extended conformations, requiring smaller average molecular areas approximately equivalent to cross sectional area of two hydrocarbon chains in a condensed film. In phase diagrams, the region for the folded forms of alpha-MAs was very limited, in contrast to the previously established behavior of ketomycolates, where complete folding predominated. Easy conversion of folded to extended conformations was indicated by thermodynamic studies of the Langmuir monolayer results and computer simulations.

Per-N-methylated analogues of an antitumor bicyclic hexapeptide RA-VII.

Penta-N-methyl and hexa-N-methyl analogues of RA-VII, an antitumor bicyclic hexapeptide of plant origin, were prepared. In the former, the nitrogens of d-Ala-1 and Ala-4 and in the latter, those of d-Ala-1, Ala-2, and Ala-4 were methylated under the phase-transfer catalysis conditions. Their solution structures were established by NOESY experiments and the crystal structures by X-ray crystallography. Those two methylated analogues showed much weaker cytotoxicity against P-388 leukemia cells than the parent RA-VII.

Challenges associated with the synthesis of unusual o-carboxamido stilbenes by the Heck protocol: Intriguing substituent effects, their toxicological and chemopreventive implications

The syntheses of fourteen unusual o-carboxamido stilbenes by the Heck protocol revealed surprising complexity related to intriguing substituent effects with mechanistic implications. The unexpected cytotoxic and chemopreventive properties also seem to be substituent dependent. For example, although stilbene 15d (with a 4-methoxy substituent) showed cytotoxicity on HT29 colon cancer cells with an IC(50) of 4.9 μM, the 3,4-dimethoxy derivative (15c) is inactive. It is interesting to observe that the 3,5-dimethoxy derivative (15e) showed remarkable chemopreventive activity in WRL-68 fetal hepatocytes, surpassing the gold standard, resveratrol. The resveratrol concentration needed to be 5 times higher than that of 15e to produce comparable elevation of NQO1.

Glycosidic alkaloids from Lupinus varius

Abstract A new glycosidic alkaloid, (−)-( trans -3′-methoxy-4′- α - l -rhamnosyloxy cinnamoyl)epilupinine, was isolated from the aerial parts of Lupinus varius , together with the eight knownalkaloids, (−)-( trans -4′- α - l -rhamnosyloxycinnamoyl) epilupinine, (+)-( trans -4′-hydroxy-3′-methoxy-cinnamoyl) epilupinine, (+)-epilupinine, (+)-epilupinine- N -oxide,(−)-multiflorine, (−)- δ 5 -dehydromultiflorine, (+)-ammodendrine and (−)-sparteine. Benzoylepilupinine was identified by GC–mass spectral analysis. The structure of the new glycosidicalkaloid was determined by chemical and spectroscopic methods.

Semisynthesis of salviandulin E analogues and their antitrypanosomal activity.

A series of analogues of salviandulin E, a rearranged neoclerodane diterpene originally isolated from Salvia leucantha (Lamiaceae), were prepared and their in vitro activity against Trypanosoma brucei brucei was evaluated with currently used therapeutic drugs as positive controls. One of the 19 compounds prepared and assayed in the present study, butanoyl 3,4-dihydrosalviandulin E analogue was found to be a possible candidate for an antitrypanosomal drug with fairly strong antitrypanosomal activity and lower cytotoxicity.