Diketopiperazine and isoindolinone alkaloids from the endophytic fungus Aspergillus sp. HAB10R12.

Four previously undescribed alkaloids, aspergillinine A-D, and four known diterpene pyrones were isolated from the potato dextrose agar (PDA) culture of Aspergillus sp. HAB10R12. The chemical structures of the isolated compounds were elucidated based on a detailed analysis of their NMR and MS data. The absolute configuration of the isolated compounds was determined by Electronic Circular Dichroism analysis coupled with computational methods. Aspergillinine A represents the first example of a diketopiperazine dipeptide containing the unnatural amino acid N-methyl kynurenine. Its absolute configuration revealed that it adopts a rather unusual conformation. Aspergillinine B represents a previously unencountered skeleton containing an isoindolinone ring. Aspergillinine C and D were similar to previously isolated diketopiperazine alkaloids, namely, lumpidin and brevianamide F, respectively. The diterpene pyrones were isolated twice previously, once from a soil-derived Aspergillus species, and once from the liquid culture of Aspergillus sp. HAB10R12. The alkaloids isolated in this study showed no antiproliferative activity when tested against HepG2 and A549 cancer cell lines.

Antibacterial and Antifungal Alkaloids from Asian Angiosperms: Distribution, Mechanisms of Action, Structure-Activity, and Clinical Potentials.

The emergence of multidrug-resistant bacteria and fungi requires the development of antibiotics and antifungal agents. This review identified natural products isolated from Asian angiosperms with antibacterial and/or antifungal activities and analyzed their distribution, molecular weights, solubility, and modes of action. All data in this review were compiled from Google Scholar, PubMed, Science Direct, Web of Science, ChemSpider, PubChem, and a library search from 1979 to 2022. One hundred and forty-one antibacterial and/or antifungal alkaloids were identified during this period, mainly from basal angiosperms. The most active alkaloids are mainly planar, amphiphilic, with a molecular mass between 200 and 400 g/mol, and a polar surface area of about 50 Å2, and target DNA and/or topoisomerase as well as the cytoplasmic membrane. 8-Acetylnorchelerythrine, cryptolepine, 8-hydroxydihydrochelerythrine, 6-methoxydihydrosanguinarine, 2'-nortiliacorinine, pendulamine A and B, rhetsisine, sampangine, tiliacorine, tryptanthrin, tylophorinine, vallesamine, and viroallosecurinine yielded MIC ≤ 1 µg/mL and are candidates for the development of lead molecules.

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.

Structure Elucidation of the spiro-Polyketide Svalbardine B from the Arctic Fungal Endophyte Poaceicola sp. E1PB with Support from Extensive ESI-MSn Interpretation.

Svalbardines A and B (1 and 2) and annularin K (3) were isolated from cultures of Poaceicola sp. E1PB, an endophyte isolated from the petals of Papaver dahlianum from Svalbard, Norway. Svalbardine A (1) is a pyrano[3,2-c]chromen-4-one, a new analogue of citromycetin. Svalbardine B (2) displays an unprecedented carbon skeleton based on a 5'-benzyl-spiro[chroman-3,7'-isochromene]-4,8'-dione core. Annularin K (3) is a hydroxylated derivative of annularin D. The structure of these new polyketides, along with those of known compounds 4-6, was established by spectrometric analysis, including extensive ESI-CID-MSn processing in the case of svalbardine B (2).

Natural diterpene pyrones: chemistry and biology.

Diterpene pyrones (DTPs) are a group of well-known, mainly fungal, natural products, first isolated in 1966. As the name indicates, they are composed of two main structural features: a diterpenyl moiety and a pyrone ring. Various names have been given to this class of metabolites; however, biogenetic evidence indicates that they originate through the same metabolic pathway. Based on their biosynthesis, which leads to differences in their structural architecture, the DTPs can be classified into three main types. In addition to their intriguing chemistry, these compounds demonstrate a wide range of biological activities rendering them a desirable target for total synthesis. To date, sixty-seven DTPs have been isolated from various fungal species, with one example originating from the plant kingdom. This review aims at unifying the classification of these compounds, in addition to presenting a detailed description of their isolation, bioactivities, biosynthesis, and total synthesis.

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.

Oligostilbenoids from the heartwood of N.†Heimii: role of non-covalent association in their biogenesis.

Four new oligostilbenes, including one dimer and three tetramers of resveratrol, that is, heimiols B-E (1-4) were isolated from the heartwood of Neobalanocarpus heimii (Dipterocarpaceae), together with thirteen known resveratrol oligomers (5-17). Examination of the structural diversity of the isolated oligostilbenes led to hypothesis of their biogenetic origin through a small number of versatile chemical pathways. These hypotheses are strongly supported by computational calculations (based on the density functional theory, DFT) that were performed to rationalize conformational re-arrangements and thus provide insights into the mechanism of oligostilbenoid biosynthesis. Non-covalent complexes are believed to drive the regio- and stereoselectivity of the oligomerization reactions.

Structure and absolute configuration of 20ß-Hydroxyprednisolone, a biotransformed product of predinisolone by the marine endophytic fungus Penicilium lapidosum.

The anti-inflammatory drug predinisolone (1) was reduced to 20ß-hydroxyprednisolone (2) by the marine endophytic fungus Penicilium lapidosum isolated from an alga. The structural elucidation of 2 was achieved by 1D- and 2D-NMR, MS, IR data. Although, 2 is a known compound previously obtained through microbial transformation, the data provided failed to prove the C20 stereochemistry. To solve this issue, DFT and TD-DFT calculations have been carried out at the B3LYP/6-31+G (d,p) level of theory in gas and solvent phase. The absolute configuration of C20 was eventually assigned by combining experimental and calculated electronic circular dichroism spectra and 3JHH chemical coupling constants.

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.

Antioxidant activity of hispidin oligomers from medicinal fungi: a DFT study.

Hispidin oligomers are styrylpyrone pigments isolated from the medicinal fungi Inonotus xeranticus and Phellinus linteus. They exhibit diverse biological activities and strong free radical scavenging activity. To rationalize the antioxidant activity of a series of four hispidin oligomers and determine the favored mechanism involved in free radical scavenging, DFT calculations were carried out at the B3P86/6-31+G (d, p) level of theory in gas and solvent. The results showed that bond dissociation enthalpies of OH groups of hispidin oligomers (ArOH) and spin density delocalization of related radicals (ArO•) are the appropriate parameters to clarify the differences between the observed antioxidant activities for the four oligomers. The effect of the number of hydroxyl groups and presence of a catechol moiety conjugated to a double bond on the antioxidant activity were determined. Thermodynamic and kinetic studies showed that the PC-ET mechanism is the main mechanism involved in free radical scavenging. The spin density distribution over phenoxyl radicals allows a better understanding of the hispidin oligomers formation.

Antioxidant properties of phenolic Schiff bases: structure-activity relationship and mechanism of action.

Phenolic Schiff bases are known for their diverse biological activities and ability to scavenge free radicals. To elucidate (1) the structure-antioxidant activity relationship of a series of thirty synthetic derivatives of 2-methoxybezohydrazide phenolic Schiff bases and (2) to determine the major mechanism involved in free radical scavenging, we used density functional theory calculations (B3P86/6-31+(d,p)) within polarizable continuum model. The results showed the importance of the bond dissociation enthalpies (BDEs) related to the first and second (BDEd) hydrogen atom transfer (intrinsic parameters) for rationalizing the antioxidant activity. In addition to the number of OH groups, the presence of a bromine substituent plays an interesting role in modulating the antioxidant activity. Theoretical thermodynamic and kinetic studies demonstrated that the free radical scavenging by these Schiff bases mainly proceeds through proton-coupled electron transfer rather than sequential proton loss electron transfer, the latter mechanism being only feasible at relatively high pH.

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 .

Time-dependent density functional theory study of UV/vis spectra of natural styrylpyrones.

Natural styrylpyrones isolated from fungi are known for various biological activities including antioxidant activity by scavenging free radicals. UV/vis spectra play an important role in elucidating chemical structures of these compounds via identification of chromophore units. With the aim of predicting the UV/vis spectra of a series of natural styrylpyrones, we tested TD-DFT, CIS and ZINDO methods in gas and in PCM solvent. The results showed that the individual or combined B3P86 and B3LYP hybrid functionals are suitable to predict the maximum wavelength absorption bands (λmax) for styrylpyrones. The structure property relationship (SPR) study emphasized the role of (i) structural parameters (e.g., hydrogen bond and the length of conjugated double bonds) and (ii) electronic descriptors (e.g., ionization potential, electronic affinity, hardness and electrophilicity) in bathochromic and hypsochromic shifts of maximum wavelength absorption bands (λmax) of styrylpyrone derivatives.

Design, synthesis, in vitro cytotoxicity evaluation and structure-activity relationship of goniothalamin analogs.

A series of six/five member (E/Z)-Goniothalamin analogs were synthesized from commercially available (3,4-dihydro-2H-pyran-2-yl)methanol/5-(hydroxymethyl)dihydrofuran-2(3H)-one in three steps with good to moderate overall yields and their cytotoxicity against lymphoblastic leukemic T cell line (Jurkat E6.1) have been evaluated. Among the synthesized analogs, (Z)-Goniothalamin appeared to be the most active in cytotoxicity (IC50 = 12 µM). Structure-activity relationship study indicates that introducing substituent in phenyl ring or replacing phenyl ring by pyridine/naphthalene, or decreasing the ring size of lactones (from six to five member) do not increase the cytotoxicity.

Regio- and stereocontrolled synthesis of oligostilbenoids: theoretical highlights at the supramolecular level.

Oligostilbenoids (e.g., ampelopsin F, viniferin, pallidol) result from homogeneous or heterogeneous coupling of monomeric stilbenoid units, leading to various chemical structures. Oligostilbenoid synthesis is regio- and stereocontrolled. To tackle this regio- and stereocontrol, a supramolecular chemistry approach is required that can be achieved by quantum chemistry. The stability of noncovalent π-stacks, formed between two stilbenoid units prior to oxidation, is accurately evaluated with density functional theory (DFT) including dispersive effects (within the DFT-D formalism). These noncovalent arrangements drive the regiocontrol. The rest of the chemical pathway is a succession of dearomatization and rearomatization stages. The thermodynamics and kinetics of the processes are calculated with classical hybrid functionals. This study allows discrimination between the two main possible chemical pathways, namely, radical-neutral and radical-radical reactions. The former appears more likely, thermodynamics and kinetics being in perfect agreement with the experimental 1:2 ratio obtained for ampelopsin F:pallidol analogues, respectively.

Diversity of endophytic bacteria in Malaysian plants as revealed by 16S rRNA encoding gene sequence based method of bacterial identification.

Bacterial endophytes do have several potential applications in pharmacy, medicine and agricultural biotech industry. The main objective of this study was to understand types of bacterial endophytes associated with dicotyledonous (dicot) and monocotyledonous (monocot) plant species. Isolation of the endophytic bacteria was performed using surface-sterilized various tissue samples, and identification of the endophytic bacterial isolates (EBIs) was completed using 16S rRNA encoding gene sequence similarity based method. In total, 996 EBIs were isolated and identified from 1055 samples of 31 monocot and 65 dicot plant species from Peninsular Malaysia. The 996 EBIs represented 71 different types of bacterial species. Twelve (12) out of 71 species are reported as endophytes for the first time. We conclude that diverse types of bacterial endophytes are associated with dicot and monocot plants, and could be useful in pharmacy, medicine and agricultural biotechnology for various potential applications.

3,5-dibenzyloxy-4'-hydroxystilbene induces early caspase-9 activation during apoptosis in human K562 chronic myelogenous leukemia cells.

A series of 22 stilbene derivatives based on resveratrol were synthesized incorporating acetoxy-, benzyloxy-, carboxy-, chloro-, hydroxy- and methoxy functional groups. We examined the cytotoxicity of these 22 stilbenes in human K562 chronic myelogenous leukemia cells. Only four compounds were cytotoxic namely 4'-hydroxy-3-methoxystilbene (15), 3'-acetoxy-4-chlorostilbene (19), 4'-hydroxy-3,5-dimethoxystilbene or pterostilbene (3) and 3,5-dibenzyloxy-4'-hydroxystilbene (28) with IC(50)s of 78 µM, 38 µM, 67 µM and 19.5 µM respectively. Further apoptosis assessment on the most potent compound, 28, confirmed that the cells underwent apoptosis based on phosphatidylserine externalization and loss of mitochondrial membrane potential. Importantly, we observed a concentration-dependent activation of caspase-9 as early as 2 hr with resultant caspase-3 cleavage in 28-induced apoptosis. Additionally, a structure-activity relationship (SAR) study proposed a possible mechanism of action for compound 28. Taken together, our data suggests that the pro-apoptotic effects of 28 involve the intrinsic mitochondrial pathway characterized by an early activation of caspase-9.

Phytochemical and cytotoxic investigations of Curcuma mangga rhizomes.

Investigations on the cytotoxic effects of the crude methanol and fractionated extracts (hexane, ethyl acetate) C. mangga against six human cancer cell lines, namely the hormone-dependent breast cell line (MCF-7), nasopharyngeal epidermoid cell line (KB), lung cell line (A549), cervical cell line (Ca Ski), colon cell lines (HCT 116 and HT-29), and one non-cancer human fibroblast cell line (MRC-5) were conducted using an in-vitro neutral red cytotoxicity assay. The crude methanol and fractionated extracts (hexane and ethyl acetate) displayed good cytotoxic effects against MCF-7, KB, A549, Ca Ski and HT-29 cell lines, but exerted no damage on the MRC-5 line. Chemical investigation from the hexane and ethyl acetate fractions resulted in the isolation of seven pure compounds, namely (E)-labda-8(17),12-dien-15,16-dial (1), (E)-15,16-bisnor-labda-8(17),11-dien-13-on (2), zerumin A (3), ß-sitosterol, curcumin, demethoxycurcumin and bis-demethoxycurcumin. Compounds 1 and 3 exhibited high cytotoxic effects against all six selected cancer cell lines, while compounds 2 showed no anti-proliferative activity on the tested cell lines. Compound 1 also demonstrated strong cytotoxicity against the normal cell line MRC-5. This paper reports for the first time the cytotoxic activities of C. mangga extracts on KB, A549, Ca Ski, HT-29 and MRC-5, and the occurrence of compound 2 and 3 in C. mangga.