Synthesis and single-molecule imaging reveal stereospecific enhancement of binding kinetics by the antitumour eEF1A antagonist SR-A3.

Ternatin-family cyclic peptides inhibit protein synthesis by targeting the eukaryotic elongation factor-1α. A potentially related cytotoxic natural product ('A3') was isolated from Aspergillus, but only 4 of its 11 stereocentres could be assigned. Here, we synthesized SR-A3 and SS-A3-two out of 128 possible A3 epimers-and discovered that synthetic SR-A3 is indistinguishable from naturally derived A3. Relative to SS-A3, SR-A3 exhibits an enhanced residence time and rebinding kinetics, as revealed by single-molecule fluorescence imaging of elongation reactions catalysed by eukaryotic elongation factor-1α in vitro. An increased residence time-stereospecifically conferred by the unique ß-hydroxyl in SR-A3-was also observed in cells. Consistent with its prolonged duration of action, thrice-weekly dosing with SR-A3 led to a reduced tumour burden and increased survival in an aggressive Myc-driven mouse lymphoma model. Our results demonstrate the potential of SR-A3 as a cancer therapeutic and exemplify an evolutionary mechanism for enhancing cyclic peptide binding kinetics via stereospecific side-chain hydroxylation.

Asperginols A and B, Diterpene Pyrones, from an Aspergillus sp. and the Structure Revision of Previously Reported Analogues.

Two new diterpene pyrones, asperginols A (1) and B (2), and four known analogues (3-6) were isolated from the endophytic fungus Aspergillus sp. HAB10R12. The structures and absolute configurations of these compounds were elucidated based on the analysis of their NMR, MS, and X-ray diffraction data. The revision of the absolute configurations at C-10, C-11, and C-14 of the known diterpene pyrones (3-6) and the determination of the configuration at the polyene side chain for compounds (4-6) were made using chemical methods and vibrational circular dichroism analysis. This group of diterpene pyrone compounds showed unique structural features including a 7/6/6 tricyclic diterpene moiety with an unusual trans-syn-trans stereochemical arrangement. Compound 6 showed moderate activity against the HT-29 colon cancer cell line.

Biosynthetic Enantiodivergence in the Eburnane Alkaloids from Kopsia.

Reexamination of the absolute configuration of recently isolated eburnane alkaloids from Malaysian Kopsia and Leuconotis species by X-ray diffraction analysis and ECD/TDDFT has revealed the existence of biosynthetic enantiodivergence. Three different scenarios are discerned with respect to the composition of the enantiomeric eburnane alkaloids in these plants: first, where the new eburnane congeners possess the same C-20, C-21 absolute configurations as the common eburnane alkaloids (eburnamonine, eburnamine, isoeburnamine, eburnamenine) occurring in the same plant; second, where the new eburnane congeners possess opposite or enantiomeric C-20, C-21 absolute configurations compared to the common eburnane alkaloids found in the same plant; and, third, where the four common eburnane alkaloids were isolated as racemic or scalemic mixtures, while the new eburnane congeners were isolated as pure enantiomers with a common C-20, C-21 configuration (20α, 21α). Additionally, the same Kopsia species (K. pauciflora) found in two different geographical locations (Peninsular Malaysia and Malaysian Borneo) showed different patterns in the composition of the enantiomeric eburnane alkaloids. Revision of the absolute configurations of a number of new eburnane congeners (previously assigned based on the assumption of a common biogenetic origin to that of the known eburnane alkaloids co-occurring in the same plant) is required based on the present results.

A Quantum Chemical and Statistical Study of Cytotoxic Activity of Compounds Isolated from Curcuma zedoaria.

A series of 21 compounds isolated from Curcuma zedoaria was subjected to cytotoxicity test against MCF7; Ca Ski; PC3 and HT-29 cancer cell lines; and a normal HUVEC cell line. To rationalize the structure-activity relationships of the isolated compounds; a set of electronic; steric and hydrophobic descriptors were calculated using density functional theory (DFT) method. Statistical analyses were carried out using simple and multiple linear regressions (SLR; MLR); principal component analysis (PCA); and hierarchical cluster analysis (HCA). SLR analyses showed that the cytotoxicity of the isolated compounds against a given cell line depend on certain descriptors; and the corresponding correlation coefficients (R2) vary from 0%-55%. MLR results revealed that the best models can be achieved with a limited number of specific descriptors applicable for compounds having a similar basic skeleton. Based on PCA; HCA and MLR analyses; active compounds were classified into subgroups; which was in agreement with the cell based cytotoxicity assay.

UV/Visible spectra of a series of natural and synthesised anthraquinones: experimental and quantum chemical approaches.

Root decoctions of anthraquinone-containing plants are often taken as postpartum tonic and aphrodisiac. Anthraquinones are known for their diverse biological activities, especially antioxidant and anticancer. A series of 35 anthraquinones was generated by isolation from Rubiaceae plants and synthesis. Their UV/vis spectrum depends on the nature and relative positions of auxochromic substituents on the basic skeleton. To predict the maximum absorption bands for the current series of anthraquinones, excited sate calculations were performed using TD-DFT, CIS, ZINDO methods. The results showed that the use of PBE0 or its combination with B3LYP and B3P86 hybrid functionals are the most suitable to reproduce accurately the experimental λMAX. The structure-property relationships (SPRs) were established based on structural and electronic properties of the anthraquinones and showed (i) the importance of the number and position of OH groups and (ii) the positive contribution of the electrophilicity and hardness as electronic descriptors on position and amplitude of the maximum absorption bands.

Chemical and pharmacognostical characterization of two Malaysian plants both known as Ajisamat

Ajisamat, an herb commonly used as an aphrodisiac in the Malaysian traditional medicine, corresponds to two different species from different families - Salacia macrophylla Blume, Celastraceae, and Prismatomeris glabra (Korth.) Valeton, Rubiaceae. Macromorphological inspection of the vegetative parts both plants reveals only a slight difference in the arrangement of the petioles. Microscopic investigation of the plants roots used as crude drugs revealed however distinctive anatomical features. Prismatic calcium oxalate crystals and banded paratracheal parenchyma are characteristics of S. macrophylla while P. glabra displays an abundance as crystals. Other features such as vessels diameters and arrangements are also of diagnostic importance. Some of these characters were also identified in the powder of thes e plant materials and proposed for diagnostic purpose. The values for extraction of ethanol and water as well as total ash, acid-insoluble ash, water-soluble ash and sulfated ash were determined for both plants. Phytochemical studies were carried out on hexane and chloroform extracts of S. macrophylla and methanolic extract of P. glabra. S. macrophylla was shown to contain highly oxidized pentacyclic triterpenes while P. glabra contains anthraquinones. The pharmacognostical and hytochemical information can be utilised as the identification tools for Salacia macrophylla and Prismatomeris glabra .

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.