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.

Palladium (II), platinum (II) and silver (I) complexes with oxazolines: Their synthesis, characterization, DFT calculation, molecular docking and antitumour effects.

Six new Pd(II), Pt(II) and Ag(I) complexes, (1);{Pd (L1)]2C6H4}2Cl4} (2); Pt(L2)(DMSO)Cl; 3; {PtL5]2C6H4}2·PhCOO-⋅11NO3-; 4; {[Pt(L4)]2C6H4}; the binuclear cyclometalated complex the polymer chain (5); {[PtL5]C6H4}·NO3-}; and the polymeric silver species (6); Zn(L6)2·AgNO3·CHCl3 were synthesized and thoroughly characterized using X-ray diffraction and spectroscopic techniques (L1=(S,S)-1,4-i-PrOx]2C6H4}2Cl4, L2=Di(2,2-bis(4R-isopropyl-4,5-dihydro-oxazol-2-yl)acetonitrile) zinc (II) (BR1);L3= 1,4-bis(4R-benzyl-4,5-dihydro-oxazol-2-yl)benzene (AR2); L4= 1,4-bis(4R-benzyl-4,5-dihydro-oxazol-2-yl)benzene，L5=1,4-bis(4R-benzyl-4,5-dihydro-oxazol-2-yl)-benzene，L6=Di(2,2-bis(4S-isopropyl-4,5-dihydrooxazol-2-yl)acetonitrile) zinc (II). Complexes 1-6 showed cytotoxic effects against human tumour cell lines, including a multidrug-resistant subline. Oxazoline and Pd complex 1 induced apoptosis in A549 cells. DFT calculations were also performed to exhibit the excellent bioactivity of complex 1 against A549, MDA-MB-231, and KB cells. Complex 1, with the best docking score and a stable interaction network within the binding site of the G-quadruplex, could stably interact with the G-quadruplex. Additionally, complex 1 was further used in the animal experiment of human lung adenocarcinoma cells in nude mice. By comparing with the model control group, the tumour volume, relative tumour volume and relative tumour proliferation rate T/C decreased significantly in the cisplatin group and compound 1 (complex 1) group.

Biology of quinoline and quinazoline alkaloids.

Quinoline and quinazoline alkaloids, two important classes of N-based heterocyclic compounds, have attracted scientific and popular interest worldwide since the 19th century. More than 600 compounds have been isolated from nature to date. To build on our two prior reviews, we reexamined the promising molecules described in previous reports and provided updated literature on novel quinoline and quinazoline alkaloids isolated over the past 5 years. This chapter reviews and discusses 205 molecules with a broad range of bioactivities, including antiparasitic and insecticidal, antibacterial and antifungal, cardioprotective, antiviral, anti-inflammatory, and other effects. 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.

Lead Optimization: Synthesis and Biological Evaluation of PBT-1 Derivatives as Novel Antitumor Agents.

Phenanthrene-based tylophorine-1 (PBT-1) was identified previously as a lead compound in an anticancer drug discovery effort based on natural Tylophora alkaloids. An expanded structural optimization using a new more efficient synthetic route provided 14 PBT-derivatives. Eleven compounds displayed obvious antiproliferative activities in cellular assays (GI50 0.55-9.32 µM). The most potent compounds 9c, 9g, and 9h (GI50 < 1 µM) contained a 7-hydroxy group on the phenanthrene B-ring in addition to a pendant piperidine E-ring with different 4-substituents. Compound 9h with NH2 as the piperidine substituent was at least 4-fold more potent against triple-negative breast cancer MDA-MB-231 than estrogen-responsible breast cancer MCF-7 cell growth. In further biological evaluations, the new active compounds induced cell cycle accumulation in the late S and G2/M phase without interfering with microtubule formation or cell morphology. These results on the optimization of the B- and E-rings of PBT-1 should benefit further development of novel antitumor agents.

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.

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.

Design, synthesis, and structure activity relationship analysis of new betulinic acid derivatives as potent HIV inhibitors.

Prior modification of betulinic acid (1), a natural product lead with promising anti-HIV activity, produced 3-O-(3',3'-dimethylsuccinyl)betulinic acid (bevirimat, 3), the first-in-class HIV maturation inhibitor. After 3-resistant variants were found during Phase I and IIa clinical trials, further modification of 3 produced 4 with improved activity against wild-type and 3-resistant HIV-1. In continued efforts to optimize 1, 63 final products have now been designed, synthesized, and evaluated for anti-HIV-1 replication activity against HIV-1NL4-3 infected MT-4 cell lines. Five known and 21 new derivatives were as or more potent than 3 (EC50 0.065 µM), while eight new derivatives were as or more potent than 4 (EC50 0.019 µM). These derivatives feature expanded structural diversity and chemical space that may improve the antiviral activity and address the growing resistance crisis. Structure-Activity Relationship (SAR) correlations were thoroughly analyzed, and a 3D Quantitative SAR model with high predictability was constructed to facilitate further rational design and development of new potent derivatives.

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].

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.

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.

Novel Betulinic Acid-Nucleoside Hybrids with Potent Anti-HIV Activity.

Novel betulinic/betulonic acid-nucleoside hybrids were synthesized as possible new anti-HIV agents. Among the synthesized hybrids, two compounds were highly effective against HIV. Compared with AZT and DSB, compounds 10a (IC50 = 0.0078 µM, CC50 = 9.6 µM) and 10b (IC50 = 0.020 µM, CC50 = 23.8 µM) showed more potent or equipotent, respectively, anti-HIV activity but displayed lower cytotoxicity.

Design and synthesis of benzylidenecyclohexenones as TrxR inhibitors displaying high anticancer activity and inducing ROS, apoptosis, and autophagy.

Oxidative therapy, a strategy that specifically increases reactive oxygen species (ROS) levels in tumor cells by disrupting the redox homeostasis has gained increasing interest. The antitumor effects of the natural product piperlongumine (PL) appear to result from its ability to increase intracellular ROS levels via inhibition of antioxidative thioredoxin reductase (TrxR). Twenty-seven benzylidenecyclohexenone-based PL analogues (2a-v and 15a-e) were designed, synthesized and evaluated for their pharmacological properties. Most of the compounds exhibited potent antiproliferative activities against five human cancer cell lines, especially against breast tumor cells. One of the most promising analogueues 2c showed 12-fold higher inhibitory activity against the thioredoxin reductase (TrxR) than PL and surpressed the expression of TrxR1 protein in breast cancer cells and inhibited TrxR enzymatic activity. In addition, 2c increased ROS levels and resulted in marked apoptosis by regulating apoptosis-related proteins expressed in the breast cancer cells. Compound 2c also triggered the formation of autophagosomes and autolysosomes by promoting the expression of LC3-II and Beclin-1 and diminishing the expression of LC3-I and p62 proteins. Finally, 2c displayed low acute toxicity and good inhibitory potency to tumors in mice. Overall, 2c is a promising anti-breast cancer candidate warranting further investigation.

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.

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.

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.

Novel potent antiplatelet thrombotic agent derived from biguanide for ischemic stroke.

Platelet thrombosis is the main pathogeny resulting in the low curability of ischemic stroke, a leading cause of mortality and disability worldwide. Metformin, a biguanide derivative that is the first-line oral medicine for type 2 diabetes, alleviates the severity of ischemic stroke in diabetic patients and suppresses platelet activation in experimental animal model. However, the clinical implementation of commercial biguanide analogs for stroke related to platelet thrombosis remains challenging due to its weak potency, poor pharmacokinetic characteristics and possible hypoglycemia. Here, twenty-three biguanide derivatives were designed and synthesized based on the principles of bioisosteres. These derivatives were evaluated for the activity of antiplatelet thrombosis in vivo. We found that N-trifluoromethanesulfonyl biguanide derivative, compound b10, uniquely prevented cerebral infarction as well as neuronal function injury, and significantly decrease the mortality rate of ischemic stroke in the middle cerebral artery occlusion mice without significant side effects. We verified that b10 directly inhibited platelets thrombus formation and decreased the compactness of stroke thrombi. Particularly, b10 exhibited good potency to inhibit human platelet activation including platelet aggregation, adhesion, pseudopodia formation, integrin GPIIb/IIIa activation, CD62P expression and clot retraction. Meanwhile, the pharmacokinetics assessment showed that b10 had satisfying pharmacological characteristics including a longer duration and a higher oral absorption ratio than its parent compound. In addition, b10 remarkably ameliorated not only stroke related to platelet thrombosis but also carotid artery thrombus formation. It is concluded that the novel potent antiplatelet thrombotic agent derived from biguanide is a promising candidate for stroke treatment.

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.

Wilforine resensitizes multidrug resistant cancer cells via competitive inhibition of P-glycoprotein.

BACKGROUND AND PURPOSE: Multidrug resistance (MDR) remains the main obstacle in cancer treatment and overexpression of P-glycoprotein (P-gp) is one of the most common causes of chemoresistance. The development of novel P-gp inhibitors from natural products is a prospective strategy to combat MDR cancers. Among the natural sesquiterpene compounds, sesquiterpene pyridine alkaloids exhibit various biological properties. Therefore, in the present study, we evaluated the modulatory effects of wilforine on P-gp expression and function. The molecular mechanisms and kinetic models of wilforine-mediated P-gp inhibition were further investigated. METHODS: The human P-gp stable expression cells (ABCB1/Flp-InTM-293) and human cervical cancer cells (sensitive: HeLaS3; MDR: KBvin) were used. The cell viability was assessed by SRB assay. The inhibitory effect of wilforine on P-gp efflux and the underlying mechanism were evaluated by assays for calcein-AM uptake, rhodamine123 and doxorubicin efflux, ATPase activity, real-time quantitative RT-PCR, apoptosis, and cell cycle analysis. Molecular docking was performed by the docking software CDOCKER with BIOVIA Discovery Studio 4.5 (D.S. 4.5). RESULTS: We found that wilforine significantly inhibited the efflux activity of P-gp in a concentration-dependent manner. Further kinetic analysis demonstrated that wilforine significantly inhibited P-gp efflux function by competitive inhibition and stimulated the basal P-gp ATPase activity. In addition, wilforine re-sensitized MDR cancer cells to chemotherapeutic drugs. The docking model indicated that wilforine was bound to residues of P-gp such as LEU884, LYS887, THR176 and ASN172. CONCLUSION: These results suggest a novel future therapeutic strategy for MDR cancer using wilforine as an adjuvant treatment with chemotherapy.

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.

Anti-HIV tigliane diterpenoids from Reutealis trisperma.

Bioassay-guided fractionation of the n-butanol extract from the branches and leaves of Reutealis trisperma resulted in the isolation of six undescribed (crotignoids L ~ Q) together with two known (12-deoxyphorbol-13-hexadecanoate and 12-deoxyphorbol-13-myristate) tigliane diterpenoids. Their structures, especially the absolute configurations, were determined from extensive spectroscopic studies, including 2D NMR spectra, CD data analysis and electronic circular dichroism (ECD) calculations. All isolates were tested for anti-HIV activity against HL4-3 virus in MT4 cells. Except for crotignoid Q, the remaining seven tigliane diterpenoids exhibited potent anti-HIV activity with IC50 values ranging from 0.0023 to 4.03 µM.