Syntheses and biological activities of deoxy-d-allose fatty acid ester analogs

We describe the syntheses of three different deoxy-D-allose analogs [2-deoxy-D-allose (2-DOAll), 1,2-dideoxy-D-allose (1,2-DOAll), and 1,2-didehydro-1,2-dideoxy-D-allose (1,2-DHAll)] and their fatty acid esters via regioselective lipase-catalyzed transesterification. Among them, 2-DOAll and its decanoate (2-DOAll-C10) showed higher inhibitory activity on plant growth, which is similar to D-allose (All) and its decanoate (All-C10). Bioassay results of deoxy-All-C10 on four plant species suggest that the hydroxy group at the C-1 position might be important showing growth inhibitory activity. In addition, co-addition of gibberellin (GA₃) with 1,2-DHAll-C10 and 2-DOAll-C10 recovered plant growth, suggesting that they might mainly inhibit biosynthesis of gibberellin.     

Cystamine-enkephalin dimer. Syntheses and biological activities of enkephalin analogs containing cystamine and cysteamine

A cystamine-enkephalin dimer, containing two molecules of [D-Ala2, Leu5] enkephalin cross-linked at the COOH-terminal leucine residue with cystamine, (NH2-CH2-CH2-S-)2, has been synthesized in order to examine directly the dimerization effect of an enkephalin molecule on the opiate receptor interactions. In a comparison of potencies against [3H]-[D-Ala2,D-Leu5] enkephalin (3H-DADLE) and [3H]-[D-Ala2,MePhe4,Gly-ol5] enkephalin (3H-DAGO) as delta and mu tracers, respectively, enkephalin dimer showed a very high affinity, especially for the delta opiate receptors. Dimer was almost threefold more potent than DADLE, which is one of the most utilized delta ligand to date. When the binding affinity of cystamine-dimer was compared with that of its reduced thiol-monomer, namely [D-Ala2,Leu5,cysteamine6] enkephalin, the increment in affinity was four to fivefold for both delta and mu receptors. The results strongly indicate that the dimeric enkephalin is more potent presumably due to the simultaneous interaction with the two binding sites of the opiate receptors.     

Syntheses and biological activities of sandostatin analogs containing stereochemical changes in positions 6 or 8

In a continuation of our research efforts on the design and synthesis of novel peptidomimetic structures, we have synthesized a series of sandostatin amide analogs in which stereoisomers of threonine and beta-hydroxyvaline(beta-Hyv) are employed. The analogs D-Phe1-c[Cys2-Phe3-D-Trp4-Lys5-Xaa6-Cys 7]-Xbb8-NH2 (Xaa = allo-Thr, D-allo-Thr, D-beta-Hyv, beta-Hyv, D-Thr, and Xbb = Thr or Xaa = Thr and Xbb = allo-Thr, D-allo-Thr, beta-Hyv, D-Thr) explore the effects on biological activity of stereochemical modifications and beta-methylation at positions 6 or 8. By these modifications, we examine the role of the two residues in binding to somatostatin receptors. We describe the synthesis and biological activity of these analogs. In combination with the results of the conformational analysis, this study provides new insights into the structural requirements for the binding affinity of somatostatin amide analogs to somatostatin receptors [Mattern et al., Conformational analyses of sandostatin analogs containing stereochemical changes in positions 6 or 8].     

Syntheses and biological activities of pyranyl-substituted cinnamates

Twenty-two kinds of pyranyl-substituted cinnamates were synthesized by the reaction of 4-hydroxy-6-(2-phenylethyl)-2H-pyran-2-one or 4-hydroxy-6-methyl-2H-pyran-2-one (HMP) with a variety of substituted cinnamic acids, and their antifungal and plant growth inhibitory activities were investigated. Among the compounds prepared, 6-methyl-2-oxo-2H-pyran-4-yl 3-(4-isopropylphenyl)propenoate (H5) showed the strongest antifungal activity against Rhizoctonia solani and Sclerotium dellfinii, and 6-methyl-2-oxo-2H-pyran-4-yl 3-(2-methylphenyl)propenoate (H2) had the highest plant growth inhibitory activity toward Brassica rapa.     

Syntheses and biological evaluation of ring-C modified colchicine analogs

Ring-C modified alkaloids were synthesized from colchicine using iminonitroso Diels–Alder reactions in a highly regio- and stereoselective fashion. Several analogs exhibited cytotoxic activity similar to that of colchicine itself against PC-3 and MCF-7 cancer cell lines, by serving as prodrugs of colchicine through retro Diels–Alder reactions under the assayed conditions. In vitro microtubule polymerization assays indicated that these modifications affected their interaction with tubulin.     

Syntheses and biological activities of azido ubiquinone derivatives

A general method for the synthesis of azido-ubiquinone derivatives has been developed directly by substituting one hydrogen atom on the benzoquinone ring with an azido group under weakly acidic conditions. The reaction takes several hours and the yield is generally low. The azido-ubiquinone was purified by preparative thin layer chromatography, and identified by NMR, IR and mass spectra. All the synthesized azido-ubiquinone derivatives show partial activity in mediating biological electron transfer in the dark, and show partial or complete inhibition upon photolysis.     

Syntheses and biological activities of sulfoximine-based acyclic triaryl olefins

Sulfoximine-based acyclic triaryl olefins 8 and 9 have been prepared and initial studies have been performed to determine their biological profiles. In contrast to their sulfonyl-substituted analog 2 sulfoximines 8 and 9 show low COX inhibitory activity. All compounds affect the estrogen receptors. While sulfone 2 interacts exclusively with ER β, sulfoximines 8 and 9 reveal almost equal blocking potencies for both estrogen receptors, ER α and ER β. In the tested series, triaryl olefin 9a shows the highest inhibitory activities with 91% and 80%, respectively (at 10 μM).     

Studies of peptide antibiotics. XLIV. Syntheses and biological activities of gramicidin S analogs containing delta-hydroxy-L-norvaline or glycine

The antibiotic gramicidin S (GS) has the structure of cyclo (-L-Val1-L-Orn2-L-Leu3-D-Phe4-L-Pro5-L-Val1'-L-Orn2'-L-Leu3'-D-Phe4'-L-Pro5'-) and is basic in character. Five GS analogs including [Gly1,1']-GS and the neutral [L-Hnv2,2']-GS (Hnv represents delta-hydroxynorvaline) were synthesized by the solid-phase method to evaluate the role of L-Val1,1' and L-Orn2,2' residues in GS. The hybrid analogs [( Gly1]-GS and [L-Hnv2]-GS) and [D-Tyr4,4']-GS showed high antibacterial activities, whereas [Gly1,1']-GS and [L-Hnv2,2']-GS possessed no activity. Inhibitory effects by these analogs for the adsorption of 14C-labeled GS on cells of bacteria sensitive to GS were determined. The structure-activity relationship of GS is discussed on the basis of the results on these GS analogs.     

Syntheses of branched-chain sugars with push-pull functionality

The reaction of methyl 4,6-O-benzylidene-3(2)-deoxy-- -erythro-hexopyranosid-2(3)-ulose with carbon disulfide, alkyl iodide, and sodium hydride gave methyl 4,6-O-benzylidene-3(2)-[bis(alkylthio)methylene]-3(2)-deoxy-- -erythro-hexopyranosid-2(3)-uloses. Methyl 4,6-O-benzylidene-2-[bis(methylthio)methylene]-2-deoxy-- -erythro-hexopyranosid-3-ulose (5) reacted with aromatic amines to give, in a rearrangement process, N-aryl-2-aryliminomethyl-4,6-O-benzylidene-2-deoxy-- -erythro-hex-1-enopyranosylamin-3-uloses. The reaction of 5 which hydrazine hydrate afforded 5-methylthio-(methyl-4,6-O-benzylidene-2,3-dideoxy-- -erythro-hexopyranosido)[3,2-c]pyrazole.     

Dehydrophenylalanyl analogs of bradykinin: Synthesis and biological activities

We have synthesized three analogs of the potent vasodilator peptide bradykinin, ArgProProGlyPhe SerProPheArg (BK), containing dehydrophenylalanine (Δ^zPhe) in place of the phenylalanyl residues at positions 5 and/or 8. The analogs, [Δ^zPhe⁵]BK, [Δ^zPhe⁸]BK, and [Δ^zPhe^5,8]BK, were assayed for their effects on isolated smooth muscle tissues and on the systemic arterial blood pressure of rats. In these assays [Δ^zPhe⁵]BK showed considerably high biological activities, particularly in terms of its blood pressure-lowering effects, being over 23 times more potent than BK when given intravenously. [Δ^zPhe⁸]BK was less potent than BK and [Δ^zPhe^5,8]BK had effects comparable to those of BK. All three synthetic analogs appear to be more resistant than BK to enzymic degradation during passage through the pulmonary vascular bed.     

Syntheses and biological activities of potent bombesin receptor antagonists.

Bombesin receptor antagonists are potential therapeutic agents due to their ability to act as inhibitors of cellular proliferation. On the basis of our hypothesis concerning the mechanism of action of gastrin associating an activating enzyme to the receptor and on the results reported in the literature, we have synthesized bombesin analogs which have been modified in the C-terminal part. Potent bombesin receptor antagonists were obtained by replacement of Leu-13 with a statyl residue or with a residue bearing an hydroxyl group in place of the carbonyl function of Leu-13. Several inhibitors were able to recognize the bombesin receptor on rat pancreatic acini and antagonized bombesin stimulated amylase secretion in the nanomolar range. These compounds were also able to recognize the bombesin receptor and to inhibit [3H] thymidine incorporation in 3T3 cells with the same potency.     

Syntheses and biological activities of fluorescent-labeled analogs of acylpolyamine toxin NPTX-594 isolated from the venom of Madagascar Joro spider

Acylpolyamine-type spider toxins are known to be potent and specific blockers against glutamate receptors (GluRs). The present study describes the syntheses and biological activities of several fluorescent-labeled analogs related to a Madagascar Joro spider toxin NPTX-594 to analyze visually the unknown interaction between spider toxins and GluRs.     

Synthesis and biological activities of cyclic ADP-carbocyclic-ribose and its analogs

An efficient synthesis of cyclic ADP-carbocyclic-ribose (2), as a stable mimic for cyclic ADP-ribose, was achieved. Treatment of N1-carbocyclic-ribosyladenosine bisphosphate derivative 10 with AgNO3 in the presence of molecular sieves 3A in pyridine gave the desired cyclic product in 93% yield, which was deprotected to give the target cyclic ADP-carbocyclic-ribose (2).     

Synthesis and evaluation of biological activities of vibsanin A analogs

Vibsanin A is an 11-membered vibsane diterpenoid and is reported to induce myeloid cell differentiation via activation of protein kinase C (PKC) without tumor-promoting activity. Therefore, vibsanin A is thought to be an attractive compound for acute myeloid leukemia (AML) therapy. In this study, we synthesized vibsanin A analogs and compared the activity of these compounds for PKC activation and myeloid cell differentiation. We found that the hydroxymethyl group in vibsanin A is an important substituent to induce differentiation of AML cells. Collectively, our results showed the biochemical features of vibsanin A and provided new insights into the development of new antileukemic drugs.     

Peroxidase-mediated in vitro metabolism of diethylstilbestrol and structural analogs with different biological activities

The comparative peroxidative metabolism of diethylstilbestrol (DES) and structurally related compounds of different biological activity was investigated in vitro with horseradish peroxidase (HRP) and hydrogen peroxide (H2O2) as a model peroxidase system: UV spectroscopy revealed the formation of p-quinone intermediates in HRP-H2O2 catalyzed incubations of DES, 3',3",5',5"-tetrafluoro-DES (TF-DES) and dimethylstilbestrol (DMS) and the tautomerization of the quinones to their dien compounds, Z,Z-dienestrol (Z,Z-DIES), tetrafluoro-dienestrol (TF-DIES) and dienmestrol (DIMS) respectively, which were characterized by HPLC and GC/MS. Z,Z-DIES, E,E-DIES, TF-DIES and DIMS were subject to further peroxidative metabolism; however, quinone intermediates were not formed in the HRP-H2O2 containing incubations according to UV spectroscopy. Similarly, hexestrol (HES), 4'-O-methyl-DES (M-DES) and 4',4"-O-dimethyl-DES (DM-DES) did not form quinone intermediates; moreover, they showed little or no apparent metabolic conversion under conditions where DES, TF-DES and DMS were readily peroxidized. However, at a 20-fold higher peroxidase concentration HES and M-DES showed metabolic conversion whereas DM-DES did not.     

Immunological and biological activities of fragments and analogs of bradykinin.

Using a number of analogs and fragments of a short-chain peptide bradykinin, a series of experiments have been carried out to assess the effect of modifications to the basic structure of the parent molecule on its myotropic and immunoreactive properties. Binding kinetics of both an antibody raised against the authentic nonapeptide and its specific biological receptor found in the guinea pig ileum were used to study these alteration effects. Peptide derivatives of bradykinin with an extension at the N-terminal (Lys- and Met-Lys-bradykinin) cross-react with the antibody raised to bradykinin 59 and 70% respectively. On the other hand, internal fragments with intact C-termini (2-9 and 3-9 bradykinin) react with this same antibody to an extent of 250 and 875% respectively, indicating that they are more potent antigens than the vasopressor molecule itself. Other internal fragments, as well as 9-substituted analogs effectively and not interact. These results indicated that the C terminal arginine of bradykinin is indeed essential in the binding mechanism with its antibody. This in turn illustrates the role of the carrier ovalbumin in the development of antiserum to the ovalbumin-toluene-diisocyanate-bradykinin complex. The physiological experiments with the guinea pig bioassay preparations lead to similar conclusions. Most internal fragments of bradykinin are devoid of activity, whereas N-terminal fragments (2-9, 3-9, and 5-9 bradykinin) have retained some activity again indicating a need for an intact arginine residue at the C-terminus of the molecule. Any modification in position 9 results in severe impairment of biological activity. Thus, the C-terminal residue of bradykinin must be conserved in order that the molecule may retain its immunological and physiological activities. Any extensions, deletions, or modifications of this site will severely retard these functions.     

Synthesis and biological activities of marine terpene-adenine hybrids and synthetic analogs

Marine sponges (Agelas sp., Raspailia sp.) produce bioactive metabolites, which can be regarded as hybrids between a terpenoid and an adenine derivative. Three sub classes are known: Agelasines, agelasimines and asmarines. Currently 19 agelasines or closely related structures, two agelasimines and 11 asmarines are published. The two agelasimines have been prepared by total synthesis, the same is true for some of the agelasines, but none of the asmarines have been synthesized so far. Agelasines are associated with antimicrobial and antineoplastic activities. Several analogs have been prepared, which are even more potent than the naturally occurring compounds, and interesting leads for treatment of for instance tuberculosis, Chagas disease and leishmaniasis have been identified. Also antifouling agents and biofilm inhibitors have been found among agelasines and analogs. Agelasines inhibits Na,K-ATPase and other ATPases, but how relevant this is for their mechanism of action, as antimicrobial and antineoplastic agents, are currently poorly understood. Agelasimines A and B display antineoplastic activity and they have the ability to inhibit smooth muscle contraction. Synthetic analogs with both antimicrobial and anticancer activities are known. Biological activities of asmarines are far less studied than those of agelasines and agelasimines, but some of them are claimed to be cytotoxic compounds.     

Syntheses and biological activities of methoxinine-analogues of the C-terminal octapeptide of cholecystokinin-pancreozymin.

The C-terminal octapeptide of cholecystokinin-pancreozymin and its analogues in which the methionine residues were successively replaced by methoxinine have been synthesized. When these analogues were tested for their gallbladder-contraction activity in an in vitro system the following relative potencies were observed: [Mox3]-CCK-PZ 8 (95%), [Mox6]-CCK-PZ 8 (5%) and [Mox3, Mox6]-CCK-PZ 8 (2%).     

Synthesis of novel sulfonamide analogs containing sulfamerazine/sulfaguanidine and their biological activities

Sulfamerazine and sulfaguanidine are clenched with p-nitrobenzoyl chloride and the products obtained are reduced to Na_xS in ethanol–water. Novel sulfonamides (6a–g and 9a–g) were synthesized by the reaction of these reduced products (4 and 8) with various sulfonyl chlorides (5a–g). The structures of these compounds were characterized using spectroscopic analysis (IR, ¹H-NMR, ¹³C-NMR and HRMS) technique. Antimicrobial activity of sulfonamides (3, 4, 7, 8, 6a–g and 9a–g) was evaluated by the agar diffusion method. These compounds showed antimicrobial activity against tested microorganism strains (Gram-positive bacteria, clinic isolate and yeast and mold). Compounds 9d, 9e, 9a, 6d and 6e showed particularly antimicrobial activity against tested Gram-positive (Bacillus cereus and B. subtilis) and Gram-negative (Enterobacter aerogenes) bacteria.