Anti-HIV Potential of Beesioside I Derivatives as Maturation Inhibitors: Synthesis, 3D-QSAR, Molecular Docking and Molecular Dynamics Simulations.

HIV-1 maturation is the final step in the retroviral lifecycle that is regulated by the proteolytic cleavage of the Gag precursor protein. As a first-in-class HIV-1 maturation inhibitor (MI), bevirimat blocks virion maturation by disrupting capsid-spacer peptide 1 (CA-SP1) cleavage, which acts as the target of MIs. Previous alterations of beesioside I (1) produced (20S,24S)-15ꞵ,16ꞵ-diacetoxy-18,24; 20,24-diepoxy-9,19-cyclolanostane-3ꞵ,25-diol 3-O-3',3'-dimethylsuccinate (3, DSC), showing similar anti-HIV potency compared to bevirimat. To ascertain the binding modes of this derivative, further modification of compound 1 was conducted. Three-dimensional quantitative structure−activity relationship (3D-QSAR) analysis combined with docking simulations and molecular dynamics (MD) were conducted. Five new derivatives were synthesized, among which compound 3b showed significant activity against HIV-1NL4-3 with an EC50 value of 0.28 µM. The developed 3D-QSAR model resulted in great predictive ability with training set (r2 = 0.99, q2 = 0.55). Molecular docking studies were complementary to the 3D-QSAR analysis, showing that DSC was differently bound to CA-SP1 with higher affinity than that of bevirimat. MD studies revealed that the complex of the ligand and the protein was stable, with root mean square deviation (RMSD) values <2.5 Å. The above results provided valuable insights into the potential of DSC as a prototype to develop new antiviral agents.

Biologically active indolizidine alkaloids.

Indolizidine alkaloids are chemical constituents isolated from various marine and terrestrial plants and animals, including but not limited to trees, fungi, ants, and frogs, with a myriad of important biological activities. In this review, we discuss the biological activity and pharmacological effects of indolizidine alkaloids and offer new avenues toward the discovery of new and better drugs based on these naturally occurring compounds.

New phorbol ester derivatives as potent anti-HIV agents.

Tigliane esters show many biological activities, including anti-HIV-1 activity. Our aim in this study was to establish structure-anti-HIV activity relationships for four series of tigliane-type diterpenoids. We synthesized and evaluated 29 new phorbol ester derivatives for anti-HIV activity and for cytotoxicity against human tumor cell lines. Among them, three derivatives, two phorbol-13-monoesters (5d and 5e) and a phorbol-12,13-diester (6a), showed significant anti-HIV activity. We found that better anti-HIV activity was often associated with a shorter acyl ester at C-13. Particularly, compounds with a phenyl ring in the ester side chain exhibited excellent anti-HIV activity and had good safety indexes. Due to its significant anti-HIV potency with a high selectivity index, phorbol-12,13-dicinnamoate (6a) was chosen as the potential candidate for further preclinical trials.

LC-MS Identification, Isolation, and Structural Elucidation of Anti-HIV Tigliane Diterpenoids from Wikstroemia lamatsoensis.

Structurally diverse tigliane diterpenoids have drawn significant research interest for drug discovery over many decades. Using LC-MS-guided fractionation and separation, the first phytochemical investigation on Wikstroemia lamatsoensis led to the isolation of eight tiglianes (1-8), including two new compounds, wikstrocin D (1) and wikstrocin E (2). The new structures were elucidated based on extensive physicochemical and spectroscopic analyses. The characteristic ESIMS/MS fragmentations of tiglianes 1-8 were also summarized. Among the isolated tiglianes, three compounds (8, 5, and 7) showed the most potent anti-HIV activity, with IC50 values of 0.18, 3.8, and 12.8 nM, respectively.

Diosgenin Derivatives as Potential Antitumor Agents: Synthesis, Cytotoxicity, and Mechanism of Action.

Thirty-two new diosgenin derivatives were designed, synthesized, and evaluated for their cytotoxic activities in three human cancer cell lines (A549, MCF-7, and HepG2) and normal human liver cells (L02) using an MTT assay in vitro. Most compounds, especially 8, 18, 26, and 30, were more potent when compared with diosgenin. The structure-activity relationship results suggested that the presence of a succinic acid or glutaric acid linker, a piperazinyl amide terminus, and lipophilic cations are all beneficial for promoting cytotoxic activity. Notably, compound 8 displayed excellent cytotoxic activity against HepG2 cells (IC50 = 1.9 µM) and showed relatively low toxicity against L02 cells (IC50 = 18.6 µM), showing some selectivity between normal and tumor cells. Studies on its cellular mechanism of action showed that compound 8 induces G0/G1 cell cycle arrest and apoptosis in HepG2 cells. Predictive studies indicated that p38α mitogen-activated protein kinase (MAPK) is the optimum target of 8 based on its 3D molecular similarity, and docking studies showed that compound 8 fits well into the active site of p38α-MAPK and forms relatively strong interactions with the surrounding amino acid residues. Accordingly, compound 8 may be used as a promising lead compound for the development of new antitumor agents.

Synthesis and in vitro anticancer activities of biotinylated derivatives of glaucocalyxin A and oridonin.

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.[Formula: see text].

Development of anti-influenza agents from natural products.

The influenza pandemic continues to threaten public health due to its high morbidity and mortality rates, despite some successes in antiviral research. Natural drugs are important alternative therapies in the treatment of and recovery from influenza and have been the subjects of intense investigation during the last few decades. Many reports have shown that the development of novel bioactive chemicals extracted from natural drugs has significant advantages. Oseltamivir is a successful case of an anti-influenza drug synthesized using two natural products, quinic acid, and shikimic acid, as starting materials. In China, traditional Chinese medicine (TCM) plays an important role in the treatment of influenza. TCM herbal extracts and prescriptions or their isolated bioactive constituents have shown significant therapeutic and preventive effects against influenza. For example, the roots of Isatis indigotica (Banlangen) fight viral infection by targeting both the virus and the host and have significantly different effects than those of synthetic chemicals. Lianhuaqingwen capsule exerts its anti-influenza activity by regulating the immune response to interfere with both viral and host reactions and might well be an alternative therapeutic option to treat influenza virus infection. This paper reviews the chemical ingredients, crude extracts, and TCM prescriptions with anti-influenza activity reported during the period of 2010-September 2019. We hope that this comprehensive review will not only fuel research on anti-influenza active natural products and TCM research but also provide a promising alternative candidate for further anti-influenza drug development.

Recent advances in natural anti-HIV triterpenoids and analogs.

The human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic is one of the world's most serious health challenges. Although combination antiretroviral therapy provides effective viral suppression, current medicines used against HIV cannot completely eradicate the infectious disease and often have associated toxicities and severe side effects in addition to causing drug resistance. Therefore, the continued development of new antiviral agents with diverse structures and novel mechanisms of action remains a vital need for the management of HIV/AIDS. Natural products are an important source of drug discovery, and certain triterpenes and their analogs have demonstrated potential as pharmaceutical precursors for the treatment of HIV. Over the past decade, natural triterpenoids and analogs have been extensively studied to find new anti-HIV drugs. This review discusses the anti-HIV triterpenoids and analogs reported during the period of 2009-2019. The article includes not only a comprehensive review of the recent anti-HIV agent development from the perspective of medicinal chemistry, but also discusses structure-activity relationship analyses of the described triterpenoids.

Biologically active isoquinoline alkaloids covering 2014-2018.

Isoquinoline alkaloids, an important class of N-based heterocyclic compounds, have attracted considerable attention from researchers worldwide since the early 19th century. Over the past 200 years, many compounds from this class were isolated, and most of them and their analogs possess various bioactivities. In this review, we survey the updated literature on bioactive alkaloids and highlight research achievements of this alkaloid class during the period of 2014-2018. We reviewed over 400 molecules with a broad range of bioactivities, including antitumor, antidiabetic and its complications, antibacterial, antifungal, antiviral, antiparasitic, insecticidal, anti-inflammatory, antioxidant, neuroprotective, and other activities. This review should provide new indications or directions for the discovery of new and better drugs from the original naturally occurring isoquinoline alkaloids.

Rapid Recognition and Targeted Isolation of Anti-HIV Daphnane Diterpenes from Daphne genkwa Guided by UPLC-MSn.

Daphnane diterpenes with a 5/7/6-tricyclic ring system exhibit potent anti-HIV activity but are found in low abundance as plant natural products. In this study, an effective approach based on mass spectrometric fragmentation pathways was conducted to specifically recognize and isolate anti-HIV compounds of this type from Daphne genkwa. Briefly, the fragmentation pathways of reference analogues were elucidated based on characteristic ion fragments of m/z 323 → 295 → 267 or m/z 253 → 238 → 197 by ultra-high-performance liquid chromatography-ion trap tandem mass spectrometry (UPLC-IT-MSn) and then applied to the differentiations of substances with or without an oxygenated group at C-12. Twenty-seven daphnane diterpenes were successfully recognized from a petroleum ether extract of D. genkwa, including some potential new compounds and isomers that could not be identified accurately only from the ion fragments. Further separation of these target compounds using high-speed countercurrent chromatography (HSCCC) and preparative HPLC led to the isolation of three new (11, 25, and 27) and 14 known compounds, whose structures were identified and confirmed based on MS, NMR, and electronic circular dichroism (ECD) spectroscopy. The isolates exhibited anti-HIV activities at nanomolar concentrations. The results demonstrated that this strategy is feasible and reliable to rapidly recognize and isolate daphnane diterpenes from D. genkwa.

Talarolactone A, an Isocoumarin Derivative Fused with Dihydrothiophene with Selective Antimigratory Activity from the Endolichenic Fungus Talaromyces sp.

A 3,4-dihydroisocoumarin derivative fused with dihydrothiophene, talarolactone A (1), and two known compounds, terreusinone (2) and 4,6-dihydroxy-5-methylphthalide (3), were isolated from Talaromyces sp. associated with Xanthoparmelia angustiphylla. The structure of 1 was deduced from extensive spectroscopic data, electronic circular dichroism calculations, and X-ray diffraction analyses. A plausible biosynthetic pathway of 1 was further proposed. Compound 1 showed selective antimigratory activity in a wound-healing assay without appreciable cytotoxic activity.

Cucurbitane-Type Triterpenoids from the Vines of Momordica charantia and Their Anti-inflammatory Activities.

Seven new cucurbitane-type triterpenoids, kuguaovins A-G (1-7), and five known ones were isolated from the rattans of wild Momordica charantia. Their structures were established by spectroscopic data analyses, including 1D and 2D NMR, IR, and MS techniques. The absolute configurations of the cucurbitanes were determined from NOESY data and partially by X-ray crystallographic analysis. In pharmacological studies, compounds 1-7 and 9-12 exhibited weak anti-inflammatory effects (IC50 = 15-35 µM), based on an anti-NO production assay.

Kalshiolin A, new lignan from Kalimeris shimadai.

The Asian plant Kalimeris shimadai has been used as food and ethnologic medicine for over a thousand years. In this study, we isolated and identified one new lignan, kalshiolin A (1), and 12 known lignans (2-13). The structures were characterized by the comprehensive analyses of spectroscopic data (HR-ESI-MS, IR, 1D, and 2D-NMR) and the absolute configuration of 1 was determined from ECD calculations. The new compound 1 was also screened for cytotoxic activity but did not show significant potency (IC50 35.9-43.3 µM) against A549, MDA-MB-231, MCF7, KB, and KB-VIN cell lines.

Design, synthesis and evaluation of antiproliferative activity of fluorinated betulinic acid.

Betulinic acid (BA), a pentacyclic triterpenoid, exhibits broad spectrum antiproliferative activity, but generally with only modest potency. To improve BA's pharmacological properties, fluorine was introduced as a single atom at C-2, creating two diastereomers, or in a trifluoromethyl group at C-3. We evaluated the impact of these groups on antiproliferative activity against five human tumor cell lines. A racemic 2-F-BA (compound 6) showed significantly improved antiproliferative activity, while each diastereomer exhibited similar effects. We also demonstrated that 2-F-BA is a topoisomerase (Topo) I and IIα dual inhibitor in cell-based and cell-free assays. A hypothetical mode of binding to the Topo I-DNA suggested a difference between the hydrogen bonding of BA and 2-F-BA to DNA, which may account for the difference in bioactivity against Topo I.

Kalshinoids A-F, Anti-inflammatory Sesquiterpenes from Kalimeris shimadae.

In a study of the potential anti-inflammatory constituents from Kalimeris shimadae, six new sesquiterpenes, kalshinoids A-F (1-6), together with 21 known compounds (7-27), were isolated. The structures and absolute configurations of the new compounds were discerned from extensive spectroscopic analysis, and the absolute configurations of kalshinoids A, B, E, and F were established by ECD calculations. Furthermore, the identified compounds were tested for anti-inflammatory activity as assessed by inhibition of tumor necrosis factor-alpha (TNF-α) in THP-1 cells. Three sesquiterpenes [kalshinoid F, 4(15)-eudesmen-1ß,7,11-triol, and 4α,10α,11-trihydroxy-1ßH,5ßH-guai-7(8)-ene] reduced levels of TNF-α in lipopolysaccharide-stimulated THP-1 cells in a concentration-dependent manner and were more potent than dexamethasone. These natural sesquiterpenes merit further investigation as possible anti-inflammatory agents.

Discovery of an Oleanolic Acid/Hederagenin-Nitric Oxide Donor Hybrid as an EGFR Tyrosine Kinase Inhibitor for Non-Small-Cell Lung Cancer.

Natural triterpenoids, such as oleanolic acid (OA) and hederagenin, display anti-lung cancer effects, and nitric oxide (NO) is associated with some oncogenic signaling pathways. Accordingly, 17 OA/hederagenin-NO donor hybrids were designed, synthesized, and evaluated against tumor cells. The most potent compound, 13, significantly inhibited the proliferation of five tumor cell lines (IC50 4.6-5.2 µM), while hederagenin inhibited the growth of only A549 tumor cells (IC50 > 10 µM). Furthermore, compound 13 showed stronger inhibitory effects on EGFR-LTC kinase activity (IC50 0.01 µM) than hederagenin (IC50 > 20 µM) and inhibited the proliferation of gefitinib-resistant H1975 (IC50 8.1 µM) and osimertinib-resistant H1975-LTC (IC50 7.6 µM) non-small-cell lung cancer (NSCLC) cells. Moreover, compound 13 produced the most NO in H1975 tumor cells, which indicated that NO may play a synergistic role. Collectively, compound 13, a novel hederagenin-NO donor hybrid with a different chemical structure from those of the current FDA-approved EGFR-targeted anti-NSCLC drugs, may be a promising lead compound for the treatment of NSCLC expressing gefitinib-resistant EGFR with a T790 M mutation or osimertinib-resistant EGFR-LTC with an L858R/T790M/C797S mutation. This work should shed light on the discovery of new anti-NSCLC drugs targeting EGFR from natural products.

Carbazole Alkaloids from Clausena anisum-olens: Isolation, Characterization, and Anti-HIV Evaluation.

Two new carbazole alkaloids (1,2) and six known carbazole alkaloids (3-8) were isolated from Clausena anisum-olens. Their structures were elucidated based on extensive spectroscopic analysis. All isolated compounds (1-8) were evaluated for their anti-HIV effects on virus replication in MT-4 lymphocytes infected by HIV-1NL4-3 Nanoluc-sec virus, and new carbazole alkaloid 1 exhibited anti-HIV activity with an EC50 value of 2.4 µg/mL and SI of 7.1.

Antiproliferative Aspidosperma-Type Monoterpenoid Indole Alkaloids from Bousigonia mekongensis Inhibit Tubulin Polymerization.

Monoterpenoid indole alkaloids are structurally diverse natural products found in plants of the family Apocynaceae. Among them, vincristine and its derivatives are well known for their anticancer activity. Bousigonia mekongensis, a species in this family, contains various monoterpenoid indole alkaloids. In the current study, fourteen known aspidosperma-type monoterpenoid indole alkaloids (1⁻14) were isolated and identified from a methanol extract of the twigs and leaves of B. mekongensis for the first time. Among them, compounds 3, 6, 9, and 13 exhibited similar antiproliferative activity spectra against A549, KB, and multidrug-resistant (MDR) KB subline KB-VIN cells with IC50 values ranging from 0.5⁻0.9 µM. The above alkaloids efficiently induced cell cycle arrest at the G2/M phase by inhibiting tubulin polymerization as well as mitotic bipolar spindle formation. Computer modeling studies indicated that compound 7 likely forms a hydrogen bond (H-bond) with α- or ß-tubulin at the colchicine site. Evaluation of the antiproliferative effects and SAR analysis suggested that a 14,15-double bond or 3α-acetonyl group is critical for enhanced antiproliferative activity. Mechanism of action studies demonstrated for the first time that compounds 3, 4, 6, 7, and 13 efficiently induce cell cycle arrest at G2/M by inhibiting tubulin polymerization by binding to the colchicine site.

New Dammarane-type Saponins from Gynostemma pentaphyllum.

Six new dammarane-type saponins, gypenosides CP1-6 (16), along with 19 known compounds 7⁻25, were isolated and characterized from the aerial parts of Gynostemma pentaphyllum. Among these compounds, eight dammarane-type saponins, 2, 5, 6, 7, 11, 12, 13, and 15, exhibited the greatest antiproliferative effects against two human tumor cell lines (A549 and HepG2).

Biologically active quinoline and quinazoline alkaloids part I.

Quinoline and quinazoline alkaloids, two important classes of N-based heterocyclic compounds, have attracted tremendous attention from researchers worldwide since the 19th century. Over the past 200 years, many compounds from these two classes were isolated from natural sources, and most of them and their modified analogs possess significant bioactivities. Quinine and camptothecin are two of the most famous and important quinoline alkaloids, and their discoveries opened new areas in antimalarial and anticancer drug development, respectively. In this review, we survey the literature on bioactive alkaloids from these two classes and highlight research achievements prior to the year 2008 (Part I). Over 200 molecules with a broad range of bioactivities, including antitumor, antimalarial, antibacterial and antifungal, antiparasitic and insecticidal, antiviral, antiplatelet, anti-inflammatory, herbicidal, antioxidant and other activities, were reviewed. This survey should provide new clues or possibilities for the discovery of new and better drugs from the original naturally occurring quinoline and quinazoline alkaloids.