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.
Tengerensine (1), isolated as a racemate and constituted from a pair of bis-benzopyrroloisoquinoline enantiomers, and tengechlorenine (2), purified as a scalemic mixture and constituted from a pair of chlorinated phenanthroindolizidine enantiomers, were isolated from the leaves of Ficus fistulosa var. tengerensis, along with three other known alkaloids. The structures of 1 and 2 were determined by spectroscopic data interpretation and X-ray diffraction analysis. The enantiomers of 1 were separated by chiral-phase HPLC, and the absolute configurations of (+)-1 and (-)-1 were established via experimental and calculated ECD data. Compound 1 is notable in being a rare unsymmetrical cyclobutane adduct and is the first example of a dimeric benzopyrroloisoquinoline alkaloid, while compound 2 represents the first naturally occurring halogenated phenanthroindolizidine alkaloid. Compound (+)-1 displayed a selective in vitro cytotoxic effect against MDA-MB-468 cells (IC50 7.4 μM), while compound 2 showed pronounced in vitro cytotoxic activity against all three breast cancer cell lines tested (MDA-MB-468, MDA-MB-231, and MCF7; IC50 values of 0.038-0.91 μM).
Seven new tropane alkaloids, including five monomeric (1-5), one dimeric (6), and one trimeric (7) 3α-nortropane ester, along with two known monomeric nortropane alkaloids (8 and 9), were isolated from the leaves and bark of Pellacalyx saccardianus. Their structures, including the absolute configuration of the enantiomeric pair of (±)-6, were elucidated by comprehensive spectroscopic analyses. Alkaloids 6 and 7 showed cytotoxicity toward human pancreatic cancer cell lines (AsPC-1, BxPC3, PANC-1, and SW1990). Alkaloids 1, 4, and 9 induced a smooth muscle relaxation effect comparable to that of atropine (Emax 106.1 ± 7.5%, 97.0 ± 5.2%, 100.9 ± 1.4%, 111.7 ± 1.7%, respectively) on isolated rat tracheal rings.
Four undescribed cucurbitacins, designated as petiolaticins A-D, and four known cucurbitacins were isolated from the bark and leaves of Elaeocarpus petiolatus (Jack) Wall. Their chemical structures were elucidated based on detailed analyses of the NMR and MS data. The absolute configuration of petiolaticin A was also determined by X-ray diffraction analysis. Petiolaticin A represents a cucurbitacin derivative incorporating a 3,4-epoxyfuranyl-bearing side chain, while petiolaticin B possesses a furopyranyl unit fused to the tetracyclic cucurbitane core structure. Petiolaticins A, B, and D were evaluated in vitro against a panel of human breast, pancreatic, and colorectal cancer cell lines. Petiolaticin A exhibited the greatest cytotoxicity against the MDA-MB-468, MDA-MB-231, MCF-7, and SW48 cell lines (IC50 7.4, 9.2, 9.3, and 4.6 μM, respectively). Additionally, petiolaticin D, 16α,23α-epoxy-3β,20β-dihydroxy-10αH,23βH-cucurbit-5,24-dien-11-one, and 16α,23α-epoxy-3β,20β-dihydroxy-10αH,23βH-cucurbit-5,24-dien-11-one 3-O-β-D-glucopyranoside were tested for their ability to inhibit cell entry of a pseudotyped virus bearing the hemagglutinin envelope protein of a highly pathogenic avian influenza virus. Petiolaticin D showed the highest inhibition (44.3%), followed by 16α,23α-epoxy-3β,20β-dihydroxy-10αH,23βH-cucurbit-5,24-dien-11-one (21.0%), and 16α,23α-epoxy-3β,20β-dihydroxy-10αH,23βH-cucurbit-5,24-dien-11-one 3-O-β-D-glucopyranoside showed limited inhibition (9.0%). These preliminary biological assays have demonstrated that petiolaticins A and D possess anticancer and antiviral properties, respectively, which warrant for further investigations.
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 systematic study was undertaken to determine the influence of ortho'-substituted nucleophilic groups (OH, NH2, or NHR) on the reactivity of anodically generated 4-methoxy- and 3,4-dimethoxystilbene cation radicals. The results showed that when ortho-substituted nucleophilic groups such as OH and NHR are present in the other ring, both direct and crossover intramolecular cation-nucleophile reactions occur to give bisbenzofurans/bisindoles or fused bisbenzopyrans/bisquinolines, respectively. Where an additional 3-methoxy substituent is present, bridged oxocine/azocine products are formed in addition to the bisbenzopyrans/bisquinolines and bisbenzofurans/bisindoles. Mechanistic rationalization of the observed behavior is presented based on a generalized pathway involving fast cation radical dimerization following electron transfer, followed by direct and crossover trapping of the benzylic cations by the ortho-substituted oxygen and nitrogen nucleophilic groups. In the instances where an additional 3-methoxy group is present, the bridged oxocine/azocine products are also formed as a result of competing aromatic substitution (Friedel-Crafts reaction). The results have shed further light and provided additional clarification on the reactivity of anodically generated stilbene cation radicals.
The present investigation represents a continuation of studies on the effect of ortho'-substitution on the reactivity of anodically generated methoxystilbene cation radicals. Whereas previous studies have focused on the effect of ortho'-substituted nucleophilic groups such as OH, NH2, CH2OH, CH2NH2, and COOH, the present study extends the investigation to ortho'-substituted vinyl and formyl groups. The results show that when the ortho'-substituent is a vinyl group, the products include a bisdihydronaphthalene derivative and a doubly bridged, dibenzofused cyclononane from direct trapping of a bis carbocation intermediate. In the presence of an additional 3-methoxy substituent, the products are the tetracyclic chrysene derivatives. When the ortho'-substituent is a nonnucleophilic formyl group, the products include fused indanylnaphthalenes and indanylbenzopyran aldehydes. When an additional 3-methoxy group is present, an unusual fused benzofluorene-dibenzoannulene product is obtained. Mechanistic rationalization for the formation of the various products is presented. The results have contributed to a deeper understanding of how the reactivity of the methoxystilbene cation radicals is affected by the nature of the ortho'-substituents.
The effect of ortho'-substituted side chains bearing nucleophilic groups such as CH2OH, CH2NHR, and CO2H on the reactivity of anodically generated 4-methoxy- and 3,4-dimethoxystilbene cation radicals was investigated, and results were compared with those of substrates where the nucleophilic groups such as OH and NHR are directly attached to the aromatic ring. It was found that when ortho'-substituted groups such as CH2OH or CH2NHR are present in the other ring, only direct intramolecular cation-nucleophile reactions occur to give bisbenzopyrans or bisisoquinolines. Crossover products (previously obtained when the ortho' substituents were OH and NH2) such as the fused benzoxepanes/fused benzoazepanes were not formed. When the ortho' substituent is COOH, direct intramolecular cation-nucleophile reaction occurs to give the corresponding bis-δ-lactones in high yield. The presence of an additional 3-methoxy substituent resulted in the formation of other fused polycyclic products due to competing aromatic substitution reactions. Reaction pathways leading to the different products and reasons for the difference in behavior shown by the present stilbenes are presented. The results have provided additional insight into the reactivity and behavior of anodically generated stilbene cation radicals.
From the leaves of Elaeocarpus tectorius (Lour.) Poir. four previously undescribed phenethylamine-containing alkaloids were isolated, namely, tectoricine, possessing an unprecedented isoquinuclidinone ring system incorporating a phenethylamine moiety, tectoraline, representing a rare alkamide incorporating two phenethylamine moieties, and tectoramidines A and B, representing the first naturally occurring trimeric and dimeric phenethylamine alkaloids incorporating an amidine function. The structures of these alkaloids were established by detailed spectroscopic analysis. The absolute configuration of tectoricine was determined by comparison of the experimental and calculated ECD spectra. Plausible biosynthetic pathways to the four alkaloids are proposed.
Eleven indole alkaloids, comprising four corynanthean, two eburnane, one aspidofractinine, one secoleuconoxine, one andranginine, and two pauciflorine type alkaloids were isolated from the stem-bark and leaf extracts of Kopsia pauciflora. Their structures were determined using NMR and MS analyses. The catharinensine type alkaloid kopsirensine B and the secoleuconoxine alkaloid arboloscine A showed moderate to weak activity in reversing MDR in vincristine-resistant KB cells. The alkaloid content was markedly different compared to that of a sample from Malaysian Borneo.
Eight new indole alkaloids (1-8) belonging to the rhazinilam-leuconolam-leuconoxine group, in addition to 52 other alkaloids, were isolated from the stem-bark extract of Leuconotis griffithii, viz., nor-rhazinicine (1), 5,21-dihydrorhazinilam-N-oxide (2), 3,14-dehydroleuconolam (3), and leuconodines A-E (4-8). The structures of these alkaloids were determined using NMR and MS analyses and in some instances confirmed by X-ray diffraction analyses. Alkaloids 1, 5, and 7 showed only moderate to weak cytotoxicity toward KB cells (IC50 12-18 μg/mL), while 8 showed moderate activity in reversing MDR in vincristine-resistant KB cells.
Leucofoline and leuconoline, representing the first members of the aspidospermatan-aspidospermatan and eburnane-sarpagine subclasses of the bisindole alkaloids, respectively, were isolated from the Malayan Leuconotis griffithii. The structures of these bisindole alkaloids were established using NMR and MS analysis, and in the case of leuconoline, confirmed by X-ray diffraction analysis. Both alkaloids showed weak cytotoxicity towards human KB cells.
Seven new indole alkaloids of the Strychnos type, leuconicines A-G (1-7), and a new eburnan alkaloid, (-)-eburnamaline (8), were isolated from the stem-bark extract of two Malayan Leuconotis species. The structures of these alkaloids were established using NMR and MS analysis and in the case of 8 also by partial synthesis. Alkaloids 1-5 reversed multidrug resistance in vincristine-resistant KB cells.
A systematic study on the FeCl3-induced oxidation of 1,2-diarylalkenes was carried out with the focus on the variation of product type as a function of aromatic substitution, as well as to compare the reactivity of stilbene cation radicals generated via Fe(III) oxidation with those generated by anodic oxidation. The aromatic substituents were found to fall into three main categories, namely those that give rise to tetralins and/or dehydrotetralins, those that give products possessing pallidol and ampelopsin F-type carbon skeletons, and last, those that give rise to trimeric products, indanes, and dehydrotetralins/tetralins. The latter are those stilbenes with a para-methoxy substituent in one ring and a para- or meta-EWG (CF3, NO2, Cl, F) in the other, and represent the most prominent departure when compared with the behavior of the same stilbenes under the conditions of anodic oxidation. Reaction pathways to rationalize the formation of the different products are presented.
A systematic study of the electrochemical oxidation of 1,2-diarylalkenes was carried out with the focus on detailed product studies and variation of product type as a function of aromatic substitution. A reinvestigation of the electrochemical oxidation of 4,4'-dimethoxystilbene under various conditions was first carried out, and all products formed were fully characterized and quantitated. This was followed by a systematic investigation of the effect of aromatic substitution on the nature and distribution of the products. The aromatic substituents were found to fall into three main categories, viz., substrates in which the nature and position of the aromatic substituents gave rise to essentially the same products as 4,4'-dimethoxystilbene, for example, tetraaryltetrahydrofurans, dehydrotetralins, and aldehydes (p-MeO or p-NMe2 on one ring and X on the other ring, where X = o-MeO or p-alkyl, or m- or p-EWG; e.g., 4-methoxy-4'-trifluoromethylstilbene); those that gave rise to a mixture of indanyl (or tetralinyl) acetamides and dehydrotetralins (or pallidols) (both or one ring substituted by alkyl groups, e.g., 4,4'-dimethylstilbene); and those where strategic placement of donor groups, such as OMe and OH, led to the formation of ampelopsin F and pallidol-type carbon skeletons (e.g., 4,3',4'-trimethoxystilbene). Reaction pathways to rationalize the formation of the different products are presented.
Two new monoterpenoid indole alkaloids, alstoscholactine (1) and alstolaxepine (2), were isolated from Alstonia scholaris. Compound 1 represents a rearranged stemmadenine alkaloid with an unprecedented C-6-C-19 connectivity, whereas compound 2 represents a 6,7- seco-angustilobine B-type alkaloid incorporating a rare γ-lactone-bridged oxepane ring system. Their structures and absolute configurations were determined by spectroscopic analyses. Compound 1 was successfully semisynthesized from 19 E-vallesamine. Compound 2 induced marked vasorelaxation in rat isolated aortic rings precontracted with phenylephrine.
Schwarzinicines A-G (1-7), representing the first examples of 1,4-diarylbutanoid-phenethylamine conjugates, were isolated from the leaves of Ficus schwarzii. The structures of these compounds were determined by detailed analysis of their MS, 1D and 2D NMR data. Compounds 1-4 exhibited pronounced vasorelaxant effects in the rat isolated aorta (Emax 106-120%; EC50 0.96-2.10 μM). However, compounds 1 and 2 showed no cytotoxic effects against A549, MCF-7, and HCT 116 human cancer cells (IC50 > 10 μM).
A total of 20 alkaloids were isolated from the leaf and stem-bark extracts of Alstonia angustiloba, of which two are hitherto unknown. One is an alkaloid of the angustilobine type (angustilobine C), while the other is a bisindole alkaloid angustiphylline, derived from the union of uleine and secovallesamine moieties. The structures of these alkaloids were established using NMR and MS analysis. Angustilobine C showed moderate cytotoxicity towards KB cells.
A concise synthesis of the 1,4-diarylbutanoid-phenethylamine alkaloids, schwarzinicines A (1) and B (2), recently isolated from Ficus schwarzii, is reported. Key steps include a Claisen condensation to assemble the 1,4-diaryl-2-butanone intermediate, followed by a reductive amination to furnish the core skeleton of the target compounds. The overall synthetic yields of 1 and 2 were 9.1% and 3.5%, respectively. Synthetic (-)-1, (+)-1 and (±)-1 exhibited comparable vasorelaxation as natural schwarzinicine A on rat isolated aortic rings, suggesting that the observed vasorelaxant effects were not influenced by the chirality at C-2.
Schwarzinicines A-D, a series of alkaloids recently discovered from Ficus schwarzii, exhibit pronounced vasorelaxant activity in rat isolated aorta. Building on this finding, a concise synthesis of schwarzinicines A and B has been reported, allowing further investigations into their biological properties. Herein, a preliminary exploration of the chemical space surrounding the structure of schwarzinicine A (1) was carried out aiming to identify structural features that are essential for vasorelaxant activity. A total of 57 analogs were synthesized and tested for vasorelaxant activity in rat isolated aorta. Both efficacy (Emax) and potency (EC50) of these analogs were compared. In addition to identifying structural features that are required for activity or associated with potency enhancement effect, four analogs showed significant potency improvements of up to 40.2-fold when compared to 1. Molecular dynamics simulation of a tetrameric 44-bound transient receptor potential canonical-6 (TRPC6) protein indicated that 44 could potentially form important interactions with the residues Glu509, Asp530, Lys748, Arg758, and Tyr521. These results may serve as a foundation for guiding further structural optimization of the schwarzinicine A scaffold, aiming to discover even more potent analogs.