Antiviral activity of some natural and synthetic sugar analogues

A number of natural and synthetic sugar analogues have been tested for their antiviral activity, using an influenza virus strain as a model. Hemagglutinating titres (HA) and cytopathic effect (CPE) were surveyed to estimate the virus production. It was found that introduction of the benzyl group into these sugars generally causes them to become antivirally active. Substitution with methyl, acetyl, uridyl and thiocyanyl groups or derivatization with azido, isopropylidene and benzylidene groups were without effect. All sugars containing the 2-deoxy-2-acetamido group were inactive.     

Hypoglycemic activity of curcumin synthetic analogues in alloxan-induced diabetic rats

The currently available therapies for type 2 diabetes have been unable to achieve normoglycemic status in the majority of patients. The reason may be attributed to the limitations of the drug itself or its side effects. In an effort to develop potent and safe oral antidiabetic agents, we evaluated the in vitro and in vivo hypoglycemic effects of 10 synthetic polyphenolic curcumin analogues on alloxan-induced male diabetic albino rats. In vitro studies showed 7-bis(3,4-dimethoxyphenyl)hepta-1,6-diene-3,5-dione (4) to be the most potential hypoglycemic agent followed by 1,5-bis(4-hydroxy-3-methoxyphenyl)penta-1,4-dien-3-one (10). Structure activity relationship (SAR) of the tested compounds was elucidated and the results were interpreted in terms of in vitro hypoglycemic activities. Furthermore, oral glucose tolerance test (OGTT) with compounds 4, 10 and reference hypoglycemic drug glipizide showed that compound 4 and glipizide had relatively similar effects on the reduction of blood glucose levels within 2?h. Thus, compound 4 might be regarded as a potential hypoglycemic agent being able to reduce glucose concentration both in vitro and in vivo.     

Antifouling activity of sponge-derived polybrominated diphenyl ethers and synthetic analogues

The antifouling (AF) activity of 2-hydroxy-4-(3-hydroxy-5-methylphenoxy)- 6-methylbenozoic acid methyl ester (1), 3,5-dibromo-2-(2',4'-dibromophenoxy)phenol (2); 3,4,5-tribromo-2-(2',4'-dibromophenoxy)phenol (3), 3,4,5-tribromo-2-(2'-bromophenoxy)phenol (4), 3,5-dibromo-2(2',4'-dibromophenoxy)phenol (5), 3,4,5,6-tetrabromo-2-(2'-bromophenoxy)phenol (6); 4-phenoxyphenol (7), 4-phenoxyaniline (9), 1-chloro-4-phenoxybenzene (10); 1-bromo-4-phenoxybenzene (13) was investigated against marine bacteria, a diatom, barnacle larvae and mussel juveniles. The naturally occurring compound 2 showed the strongest AF activity in all bioassays but lacked toxicity. It inhibited the growth of all tested bacterial strains (MIC = 0.02 - 1.52 microM) and its 50% effective concentrations (EC(50)) were 0.24 microM (diatom test), 0.66 microM (mussel test) and 1.26 microM (barnacle test). Among the commercially available derivates, compound 7 was the most active in bacterial and diatom bioassays but its activity was lower than that of compound 2. Overall, the naturally occurring compounds showed stronger activity than the commercially available analogues and could be possible future non-toxic AF candidates.     

Anti-leishmanial activity of neolignans from Virola species and synthetic analogues

Surinamensin, a neolignan isolated from Virola surinamensis, 3,4,5-trimethoxy-8-[2',6'-dimethoxy-4'-(E)-propenylphenoxy]-phenylpropane, a neolignan isolated from Virola pavonis, and 25 of its synthetic analogues or correlated substances with ether linkages and their corresponding C-8 sulphur and nitrogen analogues, were tested for activity against Leishmania donovani amastigotes and promastigotes in vitro. Some were active against L. donovani promastigotes at 30 microM but inactive against intracellular amastigotes. The natural neolignan from V. pavonis was active against promastigotes at 100 microM. The highest selective activity was found in those compounds with sulphur bridges. The beta-ketosulfide (3,4-dimethoxy)-8-(4'-methylthiophenoxy)-propiophenone produced 42% inhibition of L. donovani amastigotes in the liver of BALB/c mice at 100 mg/kg given once daily for five consecutive days (P>0.05).     

Antifouling activity of sponge-derived polybrominated diphenyl ethers and synthetic analogues

The antifouling (AF) activity of 2-hydroxy-4-(3-hydroxy-5-methylphenoxy)- 6-methylbenozoic acid methyl ester (1), 3,5-dibromo-2-(2′,4′-dibromophenoxy)phenol (2); 3,4,5-tribromo-2-(2′,4′-dibromophenoxy)phenol (3), 3,4,5-tribromo-2-(2′-bromophenoxy)phenol (4), 3,5-dibromo-2(2′,4′-dibromophenoxy)phenol (5), 3,4,5,6-tetrabromo-2-(2′-bromophenoxy)phenol (6); 4-phenoxyphenol (7), 4-phenoxyaniline (9), 1-chloro-4-phenoxybenzene (10); 1-bromo-4-phenoxybenzene (13) was investigated against marine bacteria, a diatom, barnacle larvae and mussel juveniles. The naturally occurring compound 2 showed the strongest AF activity in all bioassays but lacked toxicity. It inhibited the growth of all tested bacterial strains (MIC = 0.02 – 1.52 μM) and its 50% effective concentrations (EC₅₀) were 0.24 μM (diatom test), 0.66 μM (mussel test) and 1.26 μM (barnacle test). Among the commercially available derivates, compound 7 was the most active in bacterial and diatom bioassays but its activity was lower than that of compound 2. Overall, the naturally occurring compounds showed stronger activity than the commercially available analogues and could be possible future non-toxic AF candidates.     

Biologic activity of synthetic analogues of C5a anaphylatoxin.

The C activation fragment C5a is the most potent plasma-derived chemotactic factor known. This humoral factor induces both neutrophil and macrophage activation at low nanomolar concentrations. We have synthesized a series of C-terminal C5a analogues that exhibit all of the characteristic biologic activities of C5a. These peptides apparently contain the effector site for C5a receptor-mediated cellular activation, but express only a fraction of the potency of intact C5a. We have demonstrated the following in vitro activities for these C5a peptides: 1) ileal (guinea pig) contraction; 2) platelet (guinea pig) activation; and 3) neutrophil (human) polarization and chemotaxis. The effect of C5a peptides in vivo was evaluated by measuring enhancement in vascular permeability. Although potencies of the most effective synthetic C5a analogues were on the order of 0.01 to 0.1% that of the natural factor, our biologic data confirm that the C5a peptides are full agonists of the intact factor and may be useful substitutes for intact C5a. Furthermore, our results indicate that elongation of the C5a analogues from 10 to 19 residues in length contributes little toward enhancing or decreasing potency of the synthetic C5a analogues. Replacement of residues in the effector region by D-amino acids or by introduction of a cyclic group to reduce flexibility of the backbone decreased potency of the analogues. Substitution of His 67 by Phe in the decapeptide C5a 65-74 resulted in a significant increase in potency of the C5a analogue. The marked enhancement in potency from replacing His 67 by Phe in analogue C5a peptides identifies an important hydrophobic subsite. We conclude that site-specific amino acid modifications in or near the C-terminal effector site sequence can diminish or optimize potency of the model C5a peptides. However, there apparently are subsites on folded C5a, from regions other than the C-terminal portion of the molecule, that contribute significant receptor interactions. These subsites must be identified and incorporated into C5a model peptide designs before expression of full potency by synthetic analogues of this factor will be realized.     

Multidrug resistance-selective antiproliferative activity of Piper amide alkaloids and synthetic analogues

Twenty-five amide alkaloids (1–25) from Piper boehmeriifolium and 10 synthetic amide alkaloid derivatives (39–48) were evaluated for antiproliferative activity against eight human tumor cell lines, including chemosensitive and multidrug-resistant (MDR) cell lines. The results suggested tumor type-selectivity. 1-[7-(3,4,5-Trimethoxyphenyl)heptanoyl]piperidine (46) exhibited the best inhibitory activity (IC₅₀ = 4.94 μM) against the P-glycoprotein (P-gp)-overexpressing KBvin MDR sub-line, while it and all other tested compounds, except 9, were inactive (IC₅₀ >40 μM) against MDA-MB-231 and SK-BR-3. Structure–activity relationships (SARs) indicated that (i) 3,4,5-trimethoxy phenyl substitution is critical for selectivity against KBvin, (ii) the 4-methoxy group in this pattern is crucial for antiproliferative activity, (iii) double bonds in the side chain are not needed for activity, and (iv), in arylalkenylacyl amide alkaloids, replacement of an isobutylamino group with pyrrolidin-1-yl or piperidin-1-yl significantly improved activity. Further study on Piper amides is warranted, particularly whether side chain length affects the ability to overcome the MDR cancer phenotype.     

Biological activity of synthetic tetranuclear iron-sulphur analogues of the active sites of ferredoxins.

Two water-soluble tetranuclear iron-sulphur clusters have been synthesised which are stable under anaerobic conditions in the presence of excess thiol in aqueous solution. In such a solution, in the presence of sodium dithionite, they undergo a reversible one electron reduction to the trianion. These two clusters can replace ferredoxins in a hydrogen evolving system using $\text{Clostridium pasteurianum}$ hydrogenase with dithionite as the electron donor; we believe this is the first demonstration of such biological activity.     

Opioid activity of synthetic deltorphin II analogues and their spin labeled derivatives

Deltorphin II (Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH₂, Del II), an endogenous linear heptapeptide, is a highly selective agonist of the -opioid receptor. To study the effect of the position 4 residue (Glu) on the opioid activity of Del II, we designed and synthesized three analogues of Del II by solid-phase peptide synthesis. They were [Val⁴,Glu⁵]Del II, [Val⁴,Glu⁶]Del II and [Gly⁴,Glu⁷]Del II. To study the effect of spin labeling on peptide bioactivities, all the peptides were labeled using a free radical. The labeling material was a stable nitrogen–oxygen free radical which was linked to the N-terminal via an amide bond. We investigated the opioid bioactivities of these analogues both in vivo and in vitro, and concluded that the differences in opioid activity of Del II and its analogues were due to structural differences. When the Glu residue is at position 5 or 6, the internal hydrogen bonds in Del II are affected and there is a change in three-dimensional structure and opioid activity. The antinociceptive activity of all the peptides decreased after spin labeling. This indicates that the stable nitrogen–oxygen free radical is a dual-function spin-labeling molecule.     

Opioid activity of synthetic deltorphin II analogues and their spin labeled derivatives

Summary Deltorphin II (Tyr-D-Ala-Phe-Glu-Val-Val-Gly, NH₂, Del II), an endogenous linear heptapeptide, is a highly selective agonist of the δ-opioid receptor. To study the effect of the position 4 residue (Glu) on the opioid activity of Del II, we designed and synthesized three analogues of Del II by solid-phase peptide synthesis. They were [Val⁴, Glu⁵]Del II, [Val⁴, Glu⁶]Del II and [Gly⁴, Glu⁷]Del II. To study the effect of spin labeling on peptide bioactivities, all the peptides were labeled using a free radical. The labeling material was a stable nitrogen-oxygen free radical which was linked to the N-terminal via an amide bond. We investigated the opioid bioactivities of these analogues both in vivo and in vitro, and concluded that the differences in opioid activity of Del II and its analogues were due to structural differences. When the Glu residue is at position 5 or 6, the internal hydrogen bonds in Del II are affected and there is a change in three-dimensional structure and opioid activity. The antinociceptive activity of all the peptides decreased after spin labeling. This indicates that the stable nitrogen-oxygen free radical is a dual-function spin-labeling molecule.     

Natural abenquines and synthetic analogues: Preliminary exploration of their cytotoxic activity

In this study, we explore the cytotoxic activity of four natural abenquines (2a–d) and fourteen synthetic analogues (2e–j and 3a–h) against a panel of six human cancer cell lines using a SRB assay. It was found that most of the compounds revealed higher levels of cytotoxic activities than naturally occurring abenquines. The analogues carrying ethylpyrrolidinyl and ethylpyrimidinyl with either an acetyl group (2 h–i) or a benzoyl group (3f–g), were the most potent against all human cancer cell lines and displayed EC₅₀ between a range of 0.6–3.4 μM. Notably, of the compounds tested, compound 2i proved the most cytotoxic against both ovarian (A2780) and breast (MCF7) cells, showing EC₅₀ = 0.6 and 0.8 μM respectively. Likewise, the analogues 2i, 3f and 3 g showed strong activity against cell HT29 with EC₅₀ = 0.9 μM for these compounds.     

A synthetic approach to novel carvotacetone and antheminone analogues with anti-tumour activity

A synthetic approach to analogues of the terpenoid natural product antheminone A is described which employs (?)-quinic acid as starting material. A key conjugate addition step proved to be unpredictable regarding its stereochemical outcome however the route allowed access to two diastereoisomeric series of compounds. The results of biological assay of the toxicity of the target compounds towards non-small-cell lung cancer cell line A549 are reported.     

In vitro and in vivo antiherpetic activity of three new synthetic brassinosteroid analogues

Brassinosteroids are a novel group of steroids that appear to be ubiquitous in plants and are essential for normal plant growth and development. It has been previously reported that brassinosteroid analogues exert an antiviral activity against herpes simplex virus type 1 (HSV-1) and arenaviruses. In the present study, we report the chemical synthesis of compounds (22S,23S)-3beta-bromo-5alpha,22,23-trihydroxystigmastan-6-one (2), (22S,23S)-5alpha-fluoro-3beta-22,23-trihydroxystigmastan-6-one (3), (22S,23S)-3beta,5alpha,22,23-tetrahydroxy-stigmastan-6-one (4) as well as their antiherpetic activity both in a human conjunctive cell line (IOBA-NHC) and in the murine herpetic stromal keratitis (HSK) experimental model. All compounds prevented HSV-1 multiplication in NHC cells in a dose dependent manner when added after infection with no cytotoxicity. Administration of compounds 2, 3, and 4 to the eyes of mice at 1, 2, and 3 days post-infection delayed and reduced the incidence of HSK, consisting mainly of inflammation, vascularization, and necrosis, compared to untreated, infected mice. However, viral titers of eye washes showed no differences among samples from treated and untreated mice. Since the decrease in the percentage of mice with ocular lesions occurred 5 days after treatment had ended, we suggest that brassinosteroids 2, 3, and 4 did not exert a direct antiviral effect in vivo, but rather may play a role in immune-mediated stromal inflammation, which would explain the improvement of the clinical signs of HSK observed.     

Antisettlement activity of synthetic analogues of polymeric 3-alkylpyridinium salts isolated from the sponge Reniera sarai

Based on the high, non-toxic and reversible antifouling activity of the polymeric 3-alkylpyridinium salts isolated from the sponge Reniera sarai, the anti-settlement activity and toxicity of a series of synthetic analogues has been studied. All the test compounds were less efficient than the natural polymers, suggesting that the high and reversible anti-macrofouling activity of the natural polymers could derive from their detergent-like properties. The values obtained for EC_50sett. of inhibition of cyprid settlement and EC_50imm. as naupliar toxicity for the synthetic compounds indicate that the presence of single or multiple charges in the structure is not relevant for the antifouling activity which, conversely, is favoured by increasing the length of the alkyl chain, or by the presence of uncharged pyridine units. The compound 1,8-di(3-pyridyl)octane was the most efficient (EC_50sett.= 0.44?μg?ml^–1), although with a higher toxicity on naupliar stage of B. amphitrite than the natural polymers.     

Synthesis and endothelin receptor binding activity of synthetic analogues of RES-1149-2

A direct synthesis of analogues 6 and 7 is described. The key transformations are the addition of dibromomethyl lithium to a ketone and the subsequent mild hydrolysis to a hemiacetal.     

Antisettlement activity of synthetic analogues of polymeric 3-alkylpyridinium salts isolated from the sponge Reniera sarai

Based on the high, non-toxic and reversible antifouling activity of the polymeric 3-alkylpyridinium salts isolated from the sponge Reniera sarai, the anti-settlement activity and toxicity of a series of synthetic analogues has been studied. All the test compounds were less efficient than the natural polymers, suggesting that the high and reversible anti-macrofouling activity of the natural polymers could derive from their detergent-like properties. The values obtained for EC50sett. of inhibition of cyprid settlement and EC50imm. as naupliar toxicity for the synthetic compounds indicate that the presence of single or multiple charges in the structure is not relevant for the antifouling activity which, conversely, is favoured by increasing the length of the alkyl chain, or by the presence of uncharged pyridine units. The compound 1,8-di(3-pyridyl)octane was the most efficient (EC50sett. = 0.44 microgml(-1)), although with a higher toxicity on naupliar stage of B. amphitrite than the natural polymers.     

Structure-function study and anti-HIV activity of synthetic peptide analogues derived from viral chemokine vMIP-II

The viral macrophage inflammatory protein II (vMIP-II) shows a broad spectrum interaction with both CC and CXC chemokine receptors including CCR5 and CXCR4, two principal coreceptors for the cellular entry of human immunodeficiency virus type 1 (HIV-1). Recently, we have shown that a synthetic peptide derived from the N-terminus of vMIP-II, designated as V1, is a potent antagonist of CXCR4 but not CCR5 [Zhou, N., et al. (2000) Biochemistry 39, 3782-3787]. In this study, we synthesized a series of new peptides derived from other regions of vMIP-II and characterized their binding activities with both CXCR4 and CCR5. The results provided further support for the notion that the N-terminus of vMIP-II is the major determinant for CXCR4 recognition and that vMIP-II probably interacts with other chemokine receptors such as CCR5 with different sequence and conformational determinants. To understand the structure-function relationship of V1 peptide, its solution conformation was studied using circular dichroism spectroscopy, which showed a random conformation similar to that of the corresponding N-terminus in native vMIP-II. In addition, we synthesized a series of mutant analogues of V1 containing alanine, glycine, or phenylalanine substitution at various positions. Residues Val-1, Arg-7, and Lys-9 of V1 peptide were found to be critical for receptor interaction, because single alanine replacement at these positions dramatically decreased peptide binding to CXCR4. In contrast, alanine or phenylalanine substitution at Cys-11 led to significant enhancement in peptide affinity for CXCR4. Finally, we showed that V1 peptide inhibits HIV-1 replication in CXCR4(+) T-cell lines. These studies provide new insights into the structure-function relationship of V1 peptide and demonstrate that this peptide may be a lead for the development of therapeutic agents.     

Anticancer activity of some bisbenzimidazoles

The discovery of DNA topoisomerases has added a new dimension to the study of anticancer drugs. Bisbenzimidazole derivatives are important compounds known as DNA topoisomerase I inhibitors. In the present study, some symmetrical bisbenzimidazole derivatives were synthesized and investigated for their anticancer activity. Anticancer activity screening was applied on HT-29 (colon carcinoma) and MCF-7 (breast carcinoma) cell lines by investigation of cytotoxicity, analysis of DNA synthesis, and DNA fragmentation assays. One of the seven compounds tested showed significant cytotoxicity in both cell lines and caused DNA degradation in the HT-29 cell line.