Hybrids of the hemiasterlin analogue taltobulin and the dolastatins are potent antimicrotubule agents

The targeting of microtubules is an important mechanism for cancer chemotherapy. However, there is still a need for improved antimicrotubule agents. A number of seemingly structurally disparate peptidic natural products inhibit tubulin polymerization by binding to a region of the tubulin heterodimer close to the vinca binding site. An analogue of the naturally occurring tripeptide hemiasterlin, taltobulin (HTI-286, 3), has advanced to clinical trials. Structure-activity relationship studies of 3 have revealed critical structural elements necessary for antimicrotubule activity that correspond to comparable groups in the amino terminus tripeptide region of the dolastatins. To investigate the structural relationship between the hemiasterlins and the more complex dolastatins, hybrid compounds composed of 3 and the carboxy terminus dipeptides of dolastatin 10, or the dolastatin 15 analogue cemadotin, were synthesized. The resulting hybrid compounds were potent antimicrotubule agents, thus establishing a structural relationship between the hemiasterlins and the dolastatins. This relationship may be useful in the design of analogues having improved activity in resistant cell lines expressing the P-glycoprotein transporter, for establishing structural relationships with other classes of peptidic antimicrotubule agents, or for modeling studies of the tubulin binding site of these agents.     

Silver nanoparticles as potential antiviral agents

Virus infections pose significant global health challenges, especially in view of the fact that the emergence of resistant viral strains and the adverse side effects associated with prolonged use continue to slow down the application of effective antiviral therapies. This makes imperative the need for the development of safe and potent alternatives to conventional antiviral drugs. In the present scenario, nanoscale materials have emerged as novel antiviral agents for the possibilities offered by their unique chemical and physical properties. Silver nanoparticles have mainly been studied for their antimicrobial potential against bacteria, but have also proven to be active against several types of viruses including human imunodeficiency virus, hepatitis B virus, herpes simplex virus, respiratory syncytial virus, and monkey pox virus. The use of metal nanoparticles provides an interesting opportunity for novel antiviral therapies. Since metals may attack a broad range of targets in the virus there is a lower possibility to develop resistance as compared to conventional antivirals. The present review focuses on the development of methods for the production of silver nanoparticles and on their use as antiviral therapeutics against pathogenic viruses.     

核苷类抗病毒药物的研究进展

本文综述了近年来核苷类抗病毒药最新研究进展。介绍了核苷类抗病毒药物的种类，着重介绍了核苷化合物的改造方式。从目前临床应用的及有应用前景的各类核苷类似物出发归纳了核苷类抗病毒剂的改造原则。     

Surface-modified protein nanospheres as potential antiviral agents

A novel application of surface-modified protein nanospheres as potential antiviral agents is illustrated. By using a single-step sonochemical process, bovine serum albumin nanospheres were generated, whose surface was covalently conjugated with mercaptoethane sulfonate to chemically and electrostatically mimic cellular heparan sulfate. The nanospheres effectively inhibited HSV-1 infection.     

Quinoline derivatives: potential antiparasitic and antiviral agents

The crystal structures of closely related quinoline compounds substituted at the 2‐position by a vinyl group, either including a Cl atom [2‐(1‐chloro‐2‐methylprop‐1‐enyl)‐8‐nitroquinoline, C₁₃H₁₁ClN₂O₂, (I)] or not [2‐(2‐methylprop‐1‐enyl)‐8‐nitroquinoline, C₁₃H₁₂N₂O₂, (II)], show an important deviation of the vinyl group from coplanarity with the quinoline ring system if the Cl atom is present. The nitro group is perpendicular [in (II)] or nearly so [in (I)] to the quinoline ring system. In (II), all non‐H atoms except the nitro O atoms are located on a crystallographic mirror plane.     

Group 4 salicyloxazolines are potent polymerization catalysts

Octahedral titanium and zirconium complexes based on salicyloxazoline ligands with sterically demanding ortho-substituents provide a new family of extremely active ethene polymerization catalysts [up to 10(8) g PE (mol bar h)(-1)] which are in some cases "single site".     

Facile, chemoenzymatic synthesis of the potent antiviral compound, 2-acetonylinosine

A facile and efficient methodology for the chemoenzymatic synthesis of the antiviral compound, 2-acetonylinosine has been developed. The present synthetic strategy, which has generality, is a dramatic improvement on the methodologies currently available for the synthesis of functionalized purine nucleosides of therapeutic interest.     

Discovery of 29-O-acyl-toosendanin-based derivatives as potent anti-cancer agents

Structural modification of natural products is an effective strategy to discover potent lead compounds with improved medicinal performance. Toosendanin (TSN), a natural limonoid with diverse pharmacological properties, was selected as the starting material for structural modification to obtain more active anti-cancer agents in the current study. A library containing 25 structurally diverse derivatives (including 12 new ones) were constructed on the basis of the structure-guided modification of TSN. Subsequent cytotoxic assay of this library discovered that compounds 14, 18, and 25 showed more significant antiproliferative activity than the precursor TSN in MDA-MB-468 cell model and so as compounds 14, 17–19, 21, and 25 in Hela cell model. Among them, the new derivative 29-O-(6-chloronicotinoyl)-toosendanin (25) exhibited the most potent antiproliferative activity (IC₅₀s 0.05–0.06 μM), being more active than TSN (IC₅₀s 0.14–0.24 μM) and even the first-line drug adriamycin (IC₅₀s ～ 0.07 μM) in both tested cancer cell lines. The SARs study uncovered that the hemiacetal group, the 14,15-epoxy ring, 1-OH, 7-OH, 3-OAc, and 12-OAc were viewed as the essential active groups and the 29-OH was the critically active modification position of TSN for the enhancement of cytotoxicity. The discovering of 25 from TSN-based derivatives might serve as a lead compound for anti-cancer chemotherapy, which may shed light on rationally design TSN-based derivatives for obtaining more potent anti-tumor agents.     

Convergent synthesis of polyhalogenated quinoline C-nucleosides as potential antiviral agents

2,5,6-Trichloro-1-(beta-d-ribofuranosyl)benzimidazole (TCRB) and 2-bromo-5,6-dichloro-1-(beta-d-ribofuranosyl)benzimidazole (BDCRB) are benzimidazole nucleosides that exhibit strong and selective anti-HCMV activity. We proposed to synthesize 2-halo-6,7-dichloro-4-(beta-d-ribofuranosyl)quinolines as 6 + 6 bicyclic analogues of TCRB. The synthesis used Wittig reactions in two key steps. The first Wittig reaction coupled a fully functionalized benzene with a ribofuranose derivative to provide (Z)-6-O-(tert-butyldimethylsilyl)-1-(4,5-dichloro-2-nitrophenyl)-1,2-dideoxy-3,4-O-isopropylidene-d-allo-1-enitol (5) as the basic skeleton for the target compounds. The following electrophile-mediated intramolecular cyclization of the cis-alkene (5) was found to afford (1S,2S)-2,5-anhydro-1-bromo-6-O-(tert-butyldimethylsilyl)-1-deoxy-1-(4,5-dichloro-2-nitrophenyl)-3,4-O-isopropylidene-d-allitol (8) as the major product. This alpha-stereoselectivity was contrary to the literature precedence. A double-bond isomerization was established to be the cause of the unexpected stereochemistry. The bromo group of 8 was displaced by a hydroxyl group. Oxidation of the hydroxy group and the reduction of a phenylnitro group provided (2S)-1-(2-amino-4,5-dichlorophenyl)-2,5-anhydro-6-O-(tert-butyldimethylsilyl)-3,4-O-isopropylidene-d-allose (11), which was subjected to the second Wittig reaction with a phosphacumulene to construct 4-[5-O-(tert-butyldimethylsilyl)-2,3-O-isopropylidene-alpha-d-ribofuranosyl]-6,7-dichloroquinolin-2-one (13). Halogenation followed by deprotection of 13 and led to the synthesis of 4-(alpha-d-ribofuranosyl)-2,6,7-trichloroquinoline (17) as the major product. The 2-aminophenone alpha-nucleoside (11) was successfully anomerized to the beta-anomer (19), which led to the synthesis of the targeted 2-chloro- and 2-bromo-6,7-dichloro-4-(beta-d-ribofuranosyl)quinolines (18and 21, respectively).     

Bis-phenanthroline copper(II) phthalate complexes are potent in vitro antitumour agents with 'self-activating' metallo-nuclease and DNA binding properties

Three, structurally characterised, bis-phen Cu(II) complexes of the phthalate isomers display rapid, low micromolar in vitro cytotoxicity against a range of epithelial tumour cells. The complexes induce relaxation of supercoiled plasmid DNA in the absence of external reducing agents and display efficient CT-DNA, Poly[d(A-T)](2) and Poly[d(G-C)](2) binding.     

Uracil-coumarin based hybrid molecules as potent anti-cancer and anti-bacterial agents

In the current report, we have rationally designed a series of uracil-coumarin based bifunctional molecular hybrids roped by 1,2,3-triazole moiety. The designed compounds were synthesized and tested against a panel of six human cancer cell lines namely Colo-205, MCF-7, A-549, PA-1, PC-3 and Hela cells by Sulforhodamine B assay. The results indicated that the hybrid molecules can specifically inhibit the MCF-7 cancer cell proliferation amongst which A-2 was found to be most potent hybrid (GI₅₀ = 1.55 µM) with fluorine atom as R with two carbon chain length between triazole and coumarin moieties. Cell cycle analysis revealed that A-2 significantly arrest the G2/M phase to inhibit proliferation of MCF-7 cells. Due to its mitotic arrest, A-2 was further analyzed to predict its various binding interactions within the active site of tubulin, which revealed its best binding pattern within the vinblastine binding site. In addition to this, antibacterial potential of all the synthetics was also evaluated which resulted in two hit lead molecules A-2 (MIC = 11.7 μg/mL) and A-3 (MIC = 7.23 μg/mL) that can significantly inhibit the bacterial strain Staphylococcus aureus comparable to that of standard drug levofloxacin (MIC = 3.12 μg/mL). Binding interactions within the active site of dihydrofolate reductase (DHFR) were also streamlined by using molecular docking studies. Overall studies revealed some interesting features of synthetics to be active which stated that, the compounds with electronegative atom on R and compounds with two carbon chain length between triazole and coumarin showed best results.     

Synthesis of some novel substituted quinolines as potent analgesic agents

Summary 2-Chloroquinoline-3-carbaldehyde and 2-chloro-4-methylquinoline-3-carbaldehyde have been prepared from acetanilide and acetoacetanilidevia a Vilsmeier-Haack reaction. Upon reaction with phenyl hydrazine, hydroxylamine, urea, and thiourea in presence of acetic acid, these chloroaldehydes afforded the title compounds which exhibit a several times higher analgesic activity than noramidopyrine (NAP).

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Synthese einiger neuer substituierter Chinoline als stark analgetisch wirkende Substanzen

Zusammenfassung 2-Chlorchinolin-3-carbaldehyd und 2-Chlor-4-methylchinolin-3-carbaldehyd wurden, ausgehend von Acetanilid und Acetylacetanilid, über eineVilsmeier-Haack-Reaktion hergestellt. Reaktion dieser chlorsubstituierten Aldehyde mit Phenylhydrazin, Hydroxylamin, Harnstoff und Thioharnstoff ergab die Titelverbindungen, deren analgetische Aktivität jene von Noramidopyrin (NAP) um ein Mehrfaches übertrifft.

     

Building photoactive molecular-scale wires

Polyalkynylene groups are known to function as excellent electronic conductors at the molecular level. Such moieties have now been used to interconnect redox and photoactive transition metal oligopyridine complexes so that the efficiency of light-induced energy or electron transfer along the molecular axis can be monitored. The important issues that control the effectiveness of electronic coupling through the alkyne are discussed. In particular, attention is given to separating the effects of electron delocalization within the triplet manifold from the more general decoupling of metal-centered and charge-transfer excited states that occurs upon lowering the triplet energy. The role of the auxiliary ligands is considered, as is the effect of nuclearity. Similarly, the size of the nuclear reorganization energy has to be taken into account in a proper discussion of the photophysical properties of such systems. A second issue of importance to the design of photoelectronic devices concerns the use of interspersed groups to modulate the electronic coupling properties of the alkyne spacer. Such electron relays may be aryl hydrocarbons or platinum bis-acetylides, both groups being able to curtail electron flow along the molecular axis.     

Synthesis and biological evaluation of andrographolide derivatives as potent anti-HIV agents

A series of Andro derivatives were described and evaluated for their anti-HIV activity in vitro.Compound 10 and 16b,of which TI were>10,had some anti-HTV-l activity in vitro.Therein,compound 10 which was the best potent compound,could serve as a new lead for further development of anti-AIDS agents.     

Anticancer gold(I)-phosphine complexes as potent autophagy-inducing agents

A panel of anticancer gold(I)-phosphine complexes exhibit significant autophagy-inducing properties in cancer cells.