Synthesis of adiposin-1 and related compounds

The synthesis is described of adiposin-1 (2a), isolated from an α-d-glucosidase inhibitor complex, adiposin, produced by Streptomyces caluvs TM-521. The synthesis involved the coupling of 1,6-anhydro-4-O-(3,4-anhydro-α-d-galactopyranosyl)-β-d-glucopyranose (13) with the di-O-isopropylidene derivative (7) of dl-(1,4,$\text{6}\text{5}$)-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexenylamine. All possible diastereoisomers of the secondary amine were isolated by chromatography on silica gel. Their structures were tentatively assigned on the basis of ¹H-n.m.r. spectroscopy and optical rotation. Likewise, both the core-structure (4) of adiposin and the saturated analog (22) of 2a were synthesized.     

Synthesis of gerfelin and related analogous compounds

Gerfelin, an inhibitor of human geranylgeranyl diphosphate (GGPP) synthase that has been isolated from a culture broth of Beauveria felina QN22047, was synthesized in 4 and 3 steps starting from 2,4-dihydroxy-6-methylbenzoic acid and 3,4,5-trihydroxytoluene, respectively. An effective ligand, 2-(di-tert-butylphosphino)biphenyl, was used in the palladium-catalyzed diaryl ether-forming reaction. Five analogous compounds of gerfelin were also synthesized for a study of the structure-activity relationship.     

A synthesis of prumycin

Prumycin, 4-D-(alanylamino)-2-amino-2,4-dideoxy-L-arabinose, was synthesized from D-xylose by nine-step conversion via a key intermediate, benzyl 2,3-anhydro-4-azido-4-deoxy-β-L-ribopyranoside. An isomer of prumycin, 4-D-alanylamino-3-amino-3,4-dideoxy-L-xylose, was also synthesized from the same intermediate.     

Synthesis and pharmacological activity of aminoindanone dimers and related compounds

A series of N-substituted 3-aminoindanones were synthesised and evaluated for smooth muscle relaxant activity and mediator release inhibition effects. A low level of smooth muscle relaxant activity has been identified in all derivatives. Data have revealed that the significant mediator release inhibition effects observed are related to the nature of the amine substituents. A structure activity relationship is proposed.     

Synthesis of 4′-methoxyadenosine and related compounds

Addition of iodine and methanol to N⁶,N⁶-dibenzoyl-9(2,3-O-carbonyl-5-deoxy-β-d-erythro-pent-4-enofuranosyl)adenine (4) selectively gives N⁶,N⁶-dibenzoyl-2′,3′-O-carbonyl-5′-deoxy-5′-iodo-4′-methoxyadenosine (5). Compound 5 can be converted into 4′-methoxyadenosine via hydrolysis of the carbonate followed by benzoylation, displacement of the 5′-iodo function by benzoate ion, and hydrolysis with ammonia. Configurational assignments are based upon comparisons of ¹H- and ¹³C-n.m.r. spectra with those of previously characterised analogues in the uracil series and by borate electrophoresis. Intermediates in the above scheme have also been converted into 5′-amino-5′-deoxy-4′-methoxyadenosine, 4′-methoxy-5′-O-sulfamoyladenosine, and ethyl 4′-methoxyadenosine-5′-carboxylate, each of which is a 4′-methoxy analogue of biologically active derivatives of adenosine.     

Synthesis and antitumoral activities of marine ent-chromazonarol and related compounds.

Efficient syntheses of ent-isozonarol (6a), ent-isozonarone (7a) and ent-chromazonarol (8) from (-)-sclareol (12) are described. 6a and 7a show a significative antitumoral activity.     

Synthesis of the carbocyclic oxetanocin A1 and its related compounds

Carboxetanocin A (III) and several related compounds including carboxetanocin G (VI), 9-(3,3-bis(hydroxymethyl)adenine (X), -guanine (XI) and 9-cyclobutylguanine were prepared.     

Synthesis and biological activity of some cardiotonic compounds related to gitoxigenin

The four diastereomeric 3,16-diacetates 6, 9, 10 and 11 were prepared from gitoxin 1 by the routes shown in Schemes 1 and 2 and tested for inotropic activity in the isolated guinea-pig atrial preparation. In line with earlier findings in the digitoxigenin series, derivatives with a 3 alpha-acetoxy function, viz 9 and 10, possessed high biological activity.     

Synthesis and bioactivity of potassium beta-D-glucopyranosyl 12-hydroxy jasmonate and related compounds

Albizzia saman, a leguminous plant, is known to open its leaves in the daytime and sleep at night with the leaves folded. beta-D-Glucopyranosyl 12-hydroxyjasmonate (1) was isolated as an endogenous chemical factor controlling this leafmovement. We developed a concise synthesis of optically pure (-)-1 in 9 steps from (+)-2 with a total yield of 58%. Similarly, such analogs of 1 as epi-LCF (13), enantiomer (14), and galactoside (19) were synthesized for a structure activity relationship (SAR) study. The results of this SAR study strongly suggest that the mechanism for the leaf-closing activity of 1 would be different from that of methyl jasmonate, and also suggest the involvement of a different kind of target protein which recognizes the trans-isomer of a jasmonate derivative.     

Synthesis and antinephritic activities of quinoline-3-carboxamides and related compounds.

A series of linomide-related quinoline-3-carboxamides and their analogues was prepared and evaluated for antinephritic activities. The 6-MeS derivative 7a was highly effective in two nephritis models, namely chronic graft-versus-host disease and autoimmune MRL/l mice.     

Synthesis and antioxidant, anti-inflammatory and gastroprotector activities of anethole and related compounds

Some derivatives of trans-anethole [1-methoxy-4-(1-propenyl)-benzene] (1) were synthesized, by introducing hydroxyl groups in the double bond of the propenyl moiety. Two types of reactions were performed: (i) oxymercuration/demercuration that formed two products, the mono-hydroxyl derivative, 1-hydroxy-1-(4-methoxyphenyl)-propane (2) and in lesser extent the dihydroxyl derivative, 1,2-dihydroxy-1-(4-methoxyphenyl)-propane (3) and (ii) epoxidation with m-chloroperbenzoic acid that also led to the formation of two products, the dihydroxyl derivative (3) and the correspondent m-chloro-benzoic acid mono-ester, 1-hydroxy-1(4-methoxyphenyl)-2-m-chlorobenzoyl-propane (4). The structures of these compounds were confirmed mainly by mass, IR, 1H and 13C NMR spectral data. The activity of anethole and hydroxylated derivatives was evaluated using antioxidant, anti-inflammatory and gastroprotector tests. Compounds (2) and (3) were more active antioxidant agents than (1) and (4). In the anti-inflammatory assay, anethole showed lower activity than hydroxylated derivatives. Anethole and in lesser extent its derivatives 2 and 4 showed significant gastroprotector activity. All tested compounds do not alter significantly the total number of white blood cells.     

Synthesis and properties of an acyclic analog of 9-deazainosine and related compounds

An acyclic analogue of 9-deazainosine, 9-(2-hydroxyethoxymethyl)-9-deazahypoxanthine, and related compounds have been synthesized starting from 9-(hydroxyethyl)-9-deazahypoxanthine. The acyclo-9-deazainosine exhibited some cytotoxic activity.     

2-Phenylaminonaphthoquinones and related compounds: Synthesis,trypanocidal and cytotoxic activities

A series of new 2-aminonaphthoquinones and related compounds were synthesized and evaluated in vitro as trypanocidal and cytotoxic agents. Some tested compounds inhibited epimastigote growth and trypomastigote viability. Several compounds showed similar or higher activity and selectivity as compared with current trypanocidal drug, nifurtimox. Compound 4l exhibit higher selectivity than nifurtimox against Trypanosoma cruzi in comparison with Vero cells. Some of the synthesized quinones were tested against cancer cells and normal fibroblasts, showing that certain chemical modifications on the naphthoquinone moiety induce and excellent increase the selectivity index of the cytotoxicity (4g and 10). The results presented here show that the anti-T. cruzi activity of 2-aminonaphthoquinones derivatives can be improved by the replacement of the benzene ring by a pyridine moiety. Interestingly, the presence of a chlorine atom at C-3 and a highly lipophilic alkyl group or aromatic ring are newly observed elements that should lead to the discovery of more selective cytotoxic and trypanocidal compounds.     

Synthesis and mass spectrometry of new compounds related to the tocopherols and plastoquinones

Seven new isomers of α-tocopherol acetate have been synthesized from di- and trimethylated phenols. The compounds synthesized are: 2,5,6,7-tetramethyl-8-acetoxy-2-(4′,8′,12′-trimethyltridecyl) chroman (“ortho tocopherol acetate”), 7, and the six possible structural isomers of dimethylphytyl-1-methoxy-4-acetoxy-benzene, 12, 13, 14, 15, 18, and 19. Upon mass spectral determination, the seven synthetic compounds and natural α-tocopherol acetate produced the same fragment ions, the only differences in the spectra being in the relative intensities of some of the fragments.     

Synthesis and anticancer activity of 2-alkylaminomethyl-5-diaryl-methylenecyclopentanone hydrochlorides and related compounds

Eleven new diaryl-methylenecyclopentanone Mannich hydrochlorides and related compounds were synthesized with different modification on Mannich base and alpha,beta-unsaturated bonds. The glutathione-binding ability, glutathione-s-transferase pi (GSTpi) inhibition and antitumor effect of these compounds were compared. Compounds containing both Mannich base and alpha-unsaturated bond have GSH binding ability, GSTpi inhibitory activity and antitumor effect. Compounds without Mannich base or having a alpha-saturated bond lose GSH binding ability and the antitumor effect. Converting of Mannich base from dimethylaminomethyl group to morpholino, pyrrolidino, or piperidino-methyl groups do not evidently change the antitumor effect. However replacement of phenyl group with methylphenyl group on beta-chain significantly increases cytotoxic effect in breast cancer cells but not in immortalized mammary epithelial cells. Our data suggest that diaryl-methylenecyclopentanones represent a new category of compounds which might inhibit tumor growth through binding to glutathione or thiol proteins.     

Synthesis and antimalarial activity in vitro of potential metabolites of ferrochloroquine and related compounds

In man, the two major metabolites of the antimalarial drug chloroquine (CQ) are monodesethylchloroquine (DECQ) and didesethylchloroquine (di-DECQ). By analogy with CQ, the synthesis and the in vitro tests of some amino derivatives of ferrochloroquine (FQ), a ferrocenic analogue of CQ which are presumed to be the oxidative metabolites of FQ, are reported. Desmethylferrochloroquine 1a and didesmethylferrochloroquine 2 would be more potent against schizontocides than CQ in vitro against two strains (HB3 and Dd2) of Plasmodium falciparum. Other secondary amino derivatives have been prepared and proved to be active as antimalarial agents in vitro, too.     

Synthesis and antiproliferative activity of 2,6-diamino-9-benzyl-9-deazapurine and related compounds

Treatment of 6-bromomethyl- or 6-dibromomethyl-5-nitropyrimidine-2,4-diamine with KCN gave the same product--(2,6-diamino-5-nitropyrimidinyl)acetonitrile. Benzylation of the nitrile took place on the alpha-carbon to the cyano group preferentially affording the corresponding mono- and dibenzyl derivative, whose reductive cyclization resulted in 7-benzyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine and 7,7-dibenzyl-7H-pyrrolo[3,2-d]pyrimidine-2,4,6-triamine, respectively. Suitability of the protection of N(2) and N(4) atoms with benzyl, acetyl, or benzoyl groups was also investigated. The in vitro evaluation of cell growth inhibition on CCRF-CEM, HL-60, HeLa S3, and L1210 cell lines showed significant activity in 8 new compounds. The most potent compounds were the above mentioned 6-dibromomethyl derivative (IC(50)=0.54, 1.7, 5.0, and 1.9 molL(-1)) and 7,N(2),N(4)-tribenzyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine (IC(50)=1.9, 2.7, 7.3, and 1.0 molL(-1)).     

Synthesis and biological evaluation of novel compounds related to 1-arylnaphthalene lignans and isoquinolines

Novel compounds designed as hybrids of 1-arylnaphthalene lignans with isoquinoline alkaloids were prepared and evaluated for their cytotoxicities on human tumor cell lines, such as A549, Hela, PC-3, CNE, BEL-7404, and KB. Some of the synthetic compounds exhibited their IC50 values on selected cell lines at 10(-6) M scale. The preliminary CoMFA molecular-modelling studies of these synthetic analogues were also performed.