Ribose-modified mizoribine analogues: synthesis and biological evaluation

Synthesis, conformational analysis and antitumor evaluation of 2'- and 3'-C-methyl analogues of mizoribine (bredinine, 4-carbamoyl-1-beta-D-ribofuranosylimidazole-5-olate) are reported.     

One-pot synthesis and biological evaluation of aspergillamides and analogues

A one-pot total synthesis of aspergillamide and analogues by a solution phase Ugi multi component reaction (MCR) is described. The reaction is easily performed in 96-well plates and offers a facile access to diverse aspergillamide analogue compound libraries. The antibiotic and cytotoxic activity of these compounds is measured. Several of them are more potent than the natural product.     

Flexible synthesis and biological evaluation of novel 5-deoxyadenophorine analogues

Adenophorine and its 5-deoxy analogue have been identified as natural iminosugars with efficient glycosidase inhibitory effects. The syntheses and biological evaluation of two new series of 5-deoxyadenophorine analogues in their racemic form are reported. The compounds 12e and 13d bearing a C11 and C7 alkyl chain, respectively, were found to be potent inhibitors of the beta-glucosidase from almond with Ki near to 60 microM. The compounds 13a,d which possess a 3,4-cis stereochemistry were efficient on glucosidases but also on the beta-galactosidase, what was not observed with the 3,4-trans series 12.     

Efficient synthesis and biological evaluation of 1,3-benzenedicarbonyl dithioureas

The synthesis and biological activity of 1,3-benzenedicarbonyl dithioureas are described. Bioassay results indicated that these compounds exhibited cytotoxicity against various cancer cells. For example, compounds 4a showed the best inhibition activities against KB and CNE2 with IC₅₀ 10.72 and 9.91 μM, respectively.     

The synthesis and biological evaluation of some carbocyclic analogues of PUGNAc

The synthesis of some analogues of O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino N-phenylcarbamate, PUGNAc, an inhibitor of β-N-acetylglucosaminidases, is described. The analogues were tested against a range of β-N-acetylglucosaminidases to establish any biological activity. As well, the analogues were tested as inhibitors of a uridine diphosphate-N-acetyl-d-glucosamine: polypeptidyl transferase, OGT, a critical protein involved in the post-translational modification of nuclear and cytosolic proteins by N-acetyl-d-glucosamine.     

A practical synthesis and biological evaluation of 9-halogenated PGF analogues

A series of 9-halo PGF analogues 1-2 and 5-13 were synthesized and biologically evaluated. Among the compounds, 2 was the best EP2-receptor agonist. A practical method of synthesizing 2 via the Julia olefination of an aldehyde 3 with an optically active sulfone 4, which was prepared by Sharpless asymmetric epoxidation of 15, was developed. Other 9-halogenated PGF analogues were synthesized essentially by the same procedure and evaluated. The absolute configuration of 16-OH of 2 was determined as S by the X-ray analysis of a salt consisting of a 1/1 molar ratio of 2 and L-lysine.     

The synthesis and biological evaluation of novel bridging nucleoside analogues.

Novel bridging nucleoside analogues were prepared by cycloaddition reactions between pyranose glycals and barbiturate-derived, reactive thionoimides in modest yields. In all of the reactions conducted, the major cycloadducts obtained were the bottom faced adducts resulting from endo addition to the glycal. The adducts were stable to a variety of acidic reaction conditions and several of the compounds showed moderate activities against HIV-1 in primary human lymphocytes. One compound displayed anti-herpes simplex virus type-1 activity in Vero cells. Cytotoxicity measurements were also obtained.     

Efficient synthesis and biological evaluation of epiceanothic acid and related compounds

Epiceanothic acid (1) is a naturally occurring, but very rare pentacyclic triterpene with a unique pentacyclic triterpene (PT) structure. An efficient synthesis of 1 starting from betulin (3) has been accomplished in 12-steps with a total yield of 10% in our study. Compound 1 and selected synthetic intermediates were further evaluated as anti-HIV-1 agents, inhibitors of glycogen phosphorylase (GP), and cytotoxic agents. Compound 1 exhibited moderate HIV-1 inhibition. Most importantly, compound 5, with an opened A-ring, showed significant GP inhibitory activity with an IC₅₀ of 0.21 μM, suggesting a potential for development as an anti-diabetic agent. On the other hand, compound 12, with a closed A-ring, showed potent cytotoxicity against A549 and MCF-7 human tumor cell lines, with IC₅₀ values of 0.89 and 0.33 μM, respectively. These results suggest that the A-ring of PTs is an important pharmacophore that could be modified to involve different biological activities.     

Design, synthesis, and biological evaluation of thiophene analogues of chalcones

Chalcones are characterized by possessing an enone moiety between two aromatic rings. A series of chalcone-like agents, in which the double bond of the enone system is embedded within a thiophene ring, were synthesized and evaluated for antiproliferative activity and inhibition of tubulin assembly and colchicine binding to tubulin. The replacement of the double bond with a thiophene maintains antiproliferative activity and therefore must not significantly alter the relative conformation of the two aryl rings. The synthesized compounds were found to inhibit the growth of several cancer cell lines at nanomolar to low micromolar concentrations. In general, all compounds having significant antiproliferative activity inhibited tubulin polymerization with an IC(50)<2microM. Several of these compounds caused K562 cells to arrest in the G2/M phase of the cell cycle.     

Design, synthesis, and biological evaluation of new territrem B analogues

Some 23 analogues of the potent acetylcholinesterase (AChE) inhibitor territrem B (1) were designed, synthesized, and tested for their biological activities. Some of the new synthetic derivatives exhibited IC50 values for AChE inhibition in the upper micromolar range. Molecular-modeling studies indicated that a planar conformation seems to be crucial for AChE inhibition. The two N-atoms of the piperazine moieties in 5o, 5p, and 5r might further enhance the inhibitory effects. The cytotoxicities of selected compounds against six human tumor cell lines were also determined.     

Efficient synthesis and biological evaluation of proximicins A, B and C

A quick and efficient synthesis and the biological evaluation of promising antitumor-antibiotics proximicins A, B and C are reported. The characteristic repetitive unit of these molecules, the methyl 4-Boc-aminofuran-2-carboxylate 15, was prepared in three synthetic steps in good yield using an optimised copper-catalysed amidation method. The proximicins were evaluated for their antitumor activity using cellular methods. Proximicin B induced apoptosis in both Hodgkin's lymphoma and T-cell leukemia cell lines and proximicin C exhibited significantly high cytotoxicity against glioblastoma and breast carcinoma cells. The proximicins were also screened against Escherichia coli, Enterococcus faecalis and several strains of methicillin-and multidrug-resistant Staphylococcus aureus. Proximicin B showed noteworthy activity against antibiotic-resistant Gram-positive cocci.     

Design,synthesis and biological evaluation of fucose-truncated monosaccharide analogues of ipomoeassin F

Ipomoeassin F is a plant-derived macrocyclic glycolipid with single-digit nanomolar IC₅₀ values against cancer cell growth. In previous structure–activity relationship studies, we have demonstrated that certain modifications around the fucoside moiety did not cause significant cytotoxicity loss. To further elucidate the effect of the fucoside moiety on the biological activity, we describe here the design and synthesis of several fucose-truncated monosaccharide analogues of ipomoeassin F. Subsequent biological evaluation strongly suggests that the 6-membered ring of the fucoside moiety is essential to the overall conformation of the molecule, thereby influencing bioactivity.     

Design, synthesis and biological evaluation of 7-azatricyclodecanes: analogues of cocaine

The synthesis and biological activity of a series of azatricyclodecane analogues of cocaine are described. All compounds studied in this series exhibit nanomolar potency and good selectivity for the serotonin transporter versus the dopamine transporter.     

Design,synthesis and biological evaluation of WZ4002 analogues as EGFR inhibitors

A series of thirty two anilinopyrimidines derived from WZ4002 has been synthesized and evaluated for percentage inhibition of six different EGFR kinases using LanthaScreen binding assay method (EGFR d746 – 750) or Z’LYTE assay method (EGFR-WT, EGFR d746 – 750, EGFR T790M, EGFR T790M L858R, EGFR C797S and EGFR T790M L858R C797S). Ortho-hydroxyacetamide 10 exhibited complete inhibition of all the six kinases at 10 µM. Against the triple mutant, EGFR T790M C797S L858R, compounds 9–12 exhibited complete inhibition at 10 µM and nearly complete inhibition at 1 µM. The target compounds were also evaluated using the MTT assay to determine their cytotoxic activity against human non-small cell lung cancer cells (PC9, PC9GR and H460) and mouse leukemic cells (Ba/F3 WT and Ba/F3T 3151). Overall, 7, 9–12, 30 and 31 were found to be the most potent compounds across all five cell lines.     

Grignard-mediated synthesis and preliminary biological evaluation of novel 3-substituted farnesyl diphosphate analogues

A series of substituents was installed at the 3 position of farnesyl diphosphate through a copper-cyanide mediated coupling of a vinyl triflate with various Grignard reagents. These novel FPP mimetics were then evaluated as inhibitors of or substrates for mammalian protein farnesyl transferase. The IC50 values for these compounds range from 18 to 10,100 nm, with the 3-isopropenyl analogue being one of the most potent FPP-mimetic mFTase inhibitors yet synthesized.     

Efficient synthesis of 'redox-switched' naphthoquinone thiol-crown ethers and their biological activity evaluation

Series of naphthoquinone thiol-crown ethers had been prepared. The antibacterial, antifungal, and cytotoxic activities of these synthetic naphthoquinone thiol-crown ethers were investigated. All of the compounds tested displayed antibacterial, cytotoxic and antifungal activities. The bis-naphthoquinone thiol-crown ether 7a was the most potent inhibitor among tested analogues against Staphylococcus aureus methicillin resistance with MIC value of 2.68 microM.     

Synthesis and biological evaluation of helioxanthin analogues

Helioxanthin and analogues have been demonstrated to suppress gene expression of human hepatitis B virus. In the continuous attempt to optimize antiviral activity, various structural motifs were grafted on the helioxanthin scaffold. Many such analogues were synthesized and evaluated for their anti-hepatitis B virus activity. Structure–activity relationships of these helioxanthin derivatives are also discussed. Among these new compounds, 15 exhibits the highest activity against HBV (EC₅₀ = 0.06 μM). This compound can suppress viral surface antigen and DNA expression. Furthermore, viral RNA is also diminished while the core promoter is deactivated upon treatment by 15. A plausible working mechanism is postulated. Our results establish helioxanthin lignans as potent anti-HBV agents with unique mode of action. Since their antiviral mechanism is distinct from current nucleoside/nucleotide drugs, helioxanthin lignans constitute a potentially new class of anti-HBV agents for combination therapy.     

Synthesis and biological evaluation of hydrazidomycin analogues

Hydrazidomycin A is an unusual secondary metabolite of Streptomyces atratus that features a rare enehydrazide core. To learn more about structure–activity relationships of the reported cytotoxic and antiproliferative agent several synthetic routes were explored to synthesize a variety of hydrazidomycin derivatives. Specifically, the size of the side chains, the nature of the double bond and the polar head group were altered. Overall, fourteen analogues were tested for their cytotoxic and antiproliferative effects. Re-examination of synthetic hydrazidomycin A suggests that the antiproliferative activity is attributed to a yet unknown compound that results from degradation or rearrangement. Several of the less complex analogues, however, show antiproliferative activities against individual cancer cell lines and turned out to be more potent than hydrazidomycin A.     

Synthesis and biological evaluation of gambierol analogues

Gambierol is a polycyclic ether toxin, isolated as a toxic constituent from the marine dinoflagellate Gambierdiscus toxicus. We describe here the synthesis and biological evaluation of structural analogues of gambierol. The present preliminary structure-activity relationship studies clearly indicate that the H ring functionality and the unsaturated side chain of gambierol are crucial for its potent toxicity.