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Background: We have previously reported that a quinolizidine natural product, aloperine, and its analogs can inhibit influenza virus and/or HIV-1 at low μM concentrations. Objective: The main goal of this study was to further optimize aloperine for improved anti-influenza virus activity. Methods: Structural modifications have been focused on the N12 position of aloperine scaffold. Conventional chemical synthesis was used to obtain derivatives with improved antiviral activities. The anti-HIV and anti-influenza virus activities of the synthesized compounds were determined using an MT4 cell-based HIV-1 replication assay and an anti- influenza virus infection of MDCK cell assay, respectively. Results: Aloperine derivatives can be classified into three activity groups: those that exhibit anti-HIV activity only, anti–influenza virus only, or activity against both viruses. Aloperine optimized for potent anti-influenza activity often lost anti-HIV-1 activity, and vice versa. Compound 19 inhibited influenza virus PR8 replication with an IC50 of 0.091 μM, which is approximately 160- and 60-fold more potent than aloperine and the previously reported aloperine derivative compound 3, respectively. Conclusion: The data suggest that aloperine is a privileged scaffold that can be modified to become a selective antiviral compound with markedly improved potency against influenza virus or HIV-1.

Fourteen glaucocalyxin A biotinylated derivatives, one glaucocalyxin C biotinylated derivative, and two oridonin biotinylated derivatives were designed and synthesized. Their structures were confirmed from 1H NMR, 13C NMR and HRMS data. The derivatives were evaluated for cytotoxic activities against lung (A549), cervical cancer cell line HeLa derivative (KB), multidrug-resistant KB subline (KB-VIN), triple-negative breast (MDA-MB-231), and estrogen receptor-positive breast (MCF-7) cancer cell lines.

Two conjugates (1 and 2) of camptothecin (CPT) and 4β-anilino-4′-O-demethylepipodophyllotoxin were previously shown to exert antitumor activity through inhibition of topoisomerase I (topo I). In this current study, two novel conjugates (1E and 2E) with an open E-ring in the CPT moiety were first synthesized and evaluated for biological activity in comparison with their intact E-ring congeners. This novel class of CPT derivatives exhibits its antitumor effect against CPT-sensitive and -resistant cells, in part, by inhibiting topo I-linked DNA (TLD) religation. An intact E-ring was not essential for the inhibition of TLD religation, although conjugates with an open E-ring were less potent than the closed ring analogs. This lower religation potency resulted in decreased formation of protein-linked DNA breaks (PLDBs), and hence, less cell growth inhibition. In addition to their impact on topo I, conjugates 1E, 2, and 2E exhibited a minor inhibitory effect on topo II-induced DNA cleavage. The novel structures of 1E and 2E may present scaffolds for further development of dual function topo I and II inhibitors with improved pharmacological profiles and physicochemical properties.

Four new sesquiterpene alkaloids, emarginatine-C, emarginatine-D, emarginatine-E and emarginatinine, were isolated from Maytenus emarginata . Emarginatine-E and emarginatinine showed cytotoxicity against human KB cells (ED 50 = 2.5 and 2.1 μg ml −1 , respectively). The structural determinations and activity relationships of these new compounds, and of emarginatine-A and emarginatine-B are discussed.

Pseudolarolide J (1), a novel nortriterpene lactone, has been isolated from the seeds of Pseudolarix kaempferi and structurally characterized from spectral data and X-ray crystallographic analysis.

Two new cytotoxic diterpenes, kansuiphorin-C and -D, have been isolated from Euphorbia kansui . Their structures and stereochemistries have been established from spectral data in conjunction with X-ray crygtallographic analysis of the benzene solvate of kansuiphorin-C.

Helenalin, a natural plant product with significant antitumor activities, decreased male BDF1 mouse hepatic microsomal cytochrome P450 contents in vivo and in vitro. A single i.p. dose of 25 mg helenalin/kg body weight significantly (P less than 0.05) decreased microsomal cytochrome P450 contents and inhibited cytochrome P450-dependent mixed-function oxidase activities within 1-2 hr post-exposure. Helenalin (1.0 mM) decreased microsomal cytochrome P450 contents in vitro by 11% in the absence of NADPH and by 32% in the presence of NADPH. These in vitro and in vivo decreases in cytochrome P450 were accompanied by comparable decreases in total microsomal heme contents. Helenalin (1.0 mM) increased mouse hepatic microsomal oxygen consumption and NADPH utilization by 3.2 and 5.4 nmol/min/mg protein respectively. Helenalin (1.0 mM) significantly (P less than 0.05) increased microsomal lipid peroxidation in vitro, and this helenalin-induced increase in lipid peroxidation was inhibited completely by the addition of 0.05 mM EDTA. However, microsomal cytochrome P450 contents were equally affected by helenalin in the presence or absence of EDTA, suggesting that lipid peroxidation did not contribute to the helenalin-induced decrease in cytochrome P450. The addition of 0.05 mM hemin to microsomes treated in vitro with 1.0 mM helenalin resulted in a 58% recovery of cytochrome P450 contents. This ability of hemin to reconstitute cytochrome P450 in helenalin-treated microsomes suggests that helenalin produced a selective loss of heme from the cytochrome P450 holoprotein, and that the resulting cytochrome P450 apoprotein remained intact after helenalin treatment. The increased loss of microsomal cytochrome P450 produced by helenalin in the presence of NADPH suggests that a helenalin metabolite may be responsible for heme loss and the in vitro destruction of cytochrome P450.

Thirty-six sesquiterpene lactones and related compounds were evaluated for antimicrobial activity against six strains of bacteria. The results obtained show that the beta unsubstituted cyclopentenone ring moiety contributes to moderate antimicrobial activity against Gram positive bacteria. The corresponding saturated compounds gave a more than ten-fold decrease in activity. The significant antimicrobial activity appears to be independent of the presence or absence of an α-methylene-γ-lactone moiety. A more than ten-fold diminution in antimicrobial activity was also observed when the beta position of the cyclopentenone ring was substituted. A similar result was found when the beta unsubstituted enone system was present in a six-membered ring. Enhanced activity was obtained by esterification of the hydroxyl group of helenalin as well as epoxidation of mexicanin-A.

The stem and stem bark of Artabotrys uncinatus afforded two cytotoxic aporphine alkaloids, liriodenine and atherospermidine, as well as a novel 11 -oxoaporphine, artacinatine, which is inactive. The structure of artacinatine was elucidated from spectral data in conjunction with a single-crystal X-ray analysis.

Two cytotoxic compounds, isodiospyrin and β-amyrin, in addition to an inactive triterpene, olean-12-en-3-one, have been isolated from Diospyros morrisiana. The cytotoxic activity of isodiospyrin, which has ed 50 values of 4.9 and 0.59 μg/ml, respectively, against HCT-8 colon tumour and P-388 lymphocytic leukemia, was demonstrated for the first time. Results of single-crystal X-ray analyses of β-amyrin acetate and olean-12-en-3-one are also reported.