Relative biological activity of certain prostaglandins and their enantiomers

A series of mirror image ($\text{ent}$) forms of prostaglandins F₂ and E₂ have been compared for potency in a hamster antifertility test. In the PGF₂ series, $\text{ent}$-compounds surveyed had less potency than corresponding natural structures. For the PGE₂ series, 11α-(15S)-ent-PGE₂ methyl ester was 10-fold more potent than PGE₂. Altering the C-9 hydroxy configuration in the PGF₂ series from the natural α to β decreased potency dramatically for compounds tested.     

Synthesis and biological activity of certain 1,2,3-triazole carboxamide nucleosides related to bredinin and pyrazofurin

5-Hydroxy-1-(beta-D-ribofuranosyl)-1,2,3-triazole-4-carboxamide (II) has been prepared by direct glycosylation of the trimethylsilyl derivative of 5-hydroxy-1,2,3-triazole-4-carboxamide (IV). The use of trimethylsilyltrifluoromethane sulfonate as a catalyst and 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose in acetonitrile gave a 95% yield of a 1:1 mixture of V and VI as blocked nucleosides which were readily separated on a silica gel column. The synthesis of II was also achieved by the cycloaddition of 2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl azide with ethyl malonamate. II shows significant antiviral activity against herpes and measles virus in vitro.     

Relative biological activity of certain prostaglandins and their enantiomers.

A series of mirror image (ent) forms of prostaglandins F2 and E2 have been compared for potency in a hamster antifertility test. In the PGF2 series, ent-compounds surveyed had less potency than corresponding natural structures. For the PGE2 series, 11alpha-(15S)-ent-PGE2 methyl ester was 10-fold more potent than PGE2. Altering the C-9 hydroxy configuration in the PGF2 series from the natural alpha to beta decreased potency dramatically for compounds tested.     

Synthesis and biological activity of novel carbocyclic nucleosides

The syntheses of several novel carbocyclic nucleosides which incorporate the cyclopentene moiety of neplanocin A will be presented. These include modified pyrimidine derivatives of the very potent antitumor agent cyclopentenyl cytosine and carbocyclic analogues of the ketohexose nucleosides psicofuranine and psicofuranosyl cytosine.     

Synthesis and biological activity of modified thiopyrimidine nucleosides

N3-beta-D-glucopyranosyl, galactopyranosyl and xylopyranosyl 6-methyl-2-methylthiouracil and their 5-bromo derivatives have been synthesized by coupling an alpha-acetobromosugar with the corresponding thiouracil. The new modified thiouridine analogues were evaluated for their inhibitory activity against Human Immunodeficiency Virus (HIV) replication in MT-4 cells as well as for their cytotoxicity.     

Synthesis and biological activity of chloroethyl pyrimidine nucleosides

The synthesis and biological activity of chloroethyl pyrimidine nucleosides is presented. One of these new nucleosides analogues significantly inhibited cell proliferation, migration and invasion as tested in vitro on the A431 vulvar epidermal carcinoma cell line.     

Synthesis and biological activity of 4'-thio-L-xylofuranosyl nucleosides

A series of 4'-thio-L-xylofuranosyl nucleosides were prepared and evaluated as potential anticancer and antiviral agents. The details of a convenient and high-yielding synthesis of the carbohydrate precursor 1-O-acetyl-2,3,5-tri-O-benzyl-4-thio-L-xylofuranose (6) are presented. Proof of structure and configuration at all chiral centers of the nucleosides was obtained by proton and carbon NMR. All target compounds were evaluated in a series of human cancer cell lines in culture and as antiviral agents.     

Synthesis and antiviral activity of certain second generation methylenecyclopropane nucleosides

A second-generation series of substituted methylenecyclopropane nucleosides (MCPNs) has been synthesized and evaluated for antiviral activity against a panel of human herpesviruses, and for cytotoxicity. Although alkylated 2,6-diaminopurine analogs showed little antiviral activity, the compounds containing ether and thioether substituents at the 6-position of the purine did demonstrate potent and selective antiviral activity against several different human herpesviruses. In the 6-alkoxy series, antiviral activity depended on the length of the ether carbon chain, with the optimum chain length being about four carbon units long. For the corresponding thioethers, compounds containing secondary thioethers were more potent than those with primary thioethers.     

Enantioselective synthesis and biological evaluation of 5-o-carboranyl pyrimidine nucleosides

Base-modified carborane-containing nucleosides such as 5-o-carboranyl-2'-deoxyuridine (CDU) when combined with neutrons have potential for the treatment of certain malignancies. Lack of toxicity in various cells, high accumulation in cancer cells and intracellular phosphorylation are desirable characteristics for modified nucleosides used in boron neutron capture therapy (BNCT) for brain tumors and other malignancies. The aim of this work was to synthesize the two beta-enantiomers of several 5-o-carboranyl-containing nucleosides. These derivatives may possess favorable properties such as high lipophilicity, high transportability, the ability to be phosphorylated, and resistance to catabolism. Beta-isomers of 2',3'-dihydroxynucleosides and analogues containing a heteroatom in the sugar moiety were also synthesized. Carboranyl pyrimidine nucleosides were prepared either from the parent beta-D-nucleoside, beta-L-nucleoside, or by a coupling reaction. The dioxolane derivative 7 was prepared by a coupling reaction between protected 5-o-carboranyluracil (8, CU) and the corresponding protected heterocycle. Specific catalysts were used during the N-glycosylation process to favor the formation of the beta-isomer. Biological evaluation of these new chiral 5-o-carboranyl pyrimidine derivatives indicated that most of these compounds have low toxicity in a variety of normal and malignant cells and achieved high cellular levels in a lymphoblastoid cell line. Increasing the number of hydroxyl groups on the sugar moiety decreased the cellular accumulation and serum binding to different extents. Five compounds were identified for further biological evaluation as potential agents for BNCT.     

The synthesis of 2-pyrimidinone nucleosides and their incorporation into oligodeoxynucleotides.

The synthesis of 1-(beta-D-2'-deoxyribosyl)-2-pyrimidinone (dK) and its 5-methyl derivative (d5) from 2'-deoxycytidine or 2'-deoxythymidine, respectively, via silver oxide oxidation of 4-hydrazinopyrimidines is described. The necessary hydrazine substituted pyrimidine nucleosides have been prepared by transamination of a protected cytidine derivative or by addition/elimination reactions to an O4-sulfonated thymidine derivative. Oxidation of the 4-hydrazino pyrimidines was complicated by a competing hydrolytic reaction which generated 2'-deoxyuridine or 2'-deoxythymidine. However, in the presence of an organic base such as triethylamine, oxidation became the predominant reaction. After suitable protection and formation of the 3'-phosphoramidite derivatives, these modified nucleosides were incorporated into seven self-complementary oligodeoxynucleotides by chemical synthesis using phosphite triester methodology. Oligodeoxynucleotides were prepared such that dA-dT and dG-dC base pairs were substituted by dA-d5 or dG-dK base pairs, respectively. Both circular dichroism spectra and thermal denaturation studies were used to characterize the modified oligodeoxynucleotides.     

Synthesis of 4'-substituted nucleosides and their biological evaluation.

4'-C-Ethynyl-beta-D-arabino- and 4'-C-ethynyl-beta-D-2'-deoxy-ribo-pentofuranosyl pyrimidines were synthesized. Most of these 4'-ethynyl nucleosides showed interesting biological activities.     

Synthesis of novel 4'-C-methyl-pyrimidine nucleosides and their biological activities

Two novel 4'-C-methylnucleosides, 4'-methylBVDU 9 and 4'-methylBVaraU 10, were synthesized. The former was derived from 3',5'-di-O-acetyl-2'-deoxy-4'-C-methyluridine 12, and the latter was produced via glycosylation between 4-C-methyl-D-ribose derivative 11 and a silylated bromovinyl uracil. 4'-MethylBVDU 9 exhibited particularly potent anti-varicella-zoster virus (VZV) activity in vitro.     

The destruxins: synthesis, biosynthesis, biotransformation, and biological activity

Destruxins, secondary metabolites first reported in 1961, are cyclic hexadepsipeptides composed of an alpha-hydroxy acid and five amino acid residues. The name "destruxin" is derived from "destructor" from the species Oospora destructor, the entomopathogenic fungus from which these metabolites were first isolated. Individual destruxins differ on the hydroxy acid, N-methylation, and R group of the amino acid residues; where established, the configurations of the amino acid residues are S, and those of the hydroxy acids are R. Destruxins exhibit a wide variety of biological activities, but are best known for their insecticidal and phytotoxic activities. The great interest in destruxins derives from their potential role as virulence factors in fungi, whether such microorganisms are useful insect biocontrol agents or detrimental, causing great plant disease epidemics. Reports on isolation, chemical structure determination, total synthesis, transformation by diverse organisms, and biological activity of destruxins and related metabolites are reviewed for the first time.     

Metal based isatin-derived sulfonamides: their synthesis, characterization, coordination behavior and biological activity

Some isatin derived sulfonamides and their transition metal [Co(II), Cu(II), Ni(II), Zn(II)] complexes have been synthesized and characterized. The structure of synthesized compounds and their nature of bonding have been inferred on the basis of their physical (magnetic susceptibility and conductivity measurements), analytical (elemental analyses) and spectral (IR, (1)H NMR and (13)C NMR) properties. An octahedral geometry has been suggested for Co(II), Ni(II) and Zn(II) and square-planar for Cu(II) complexes. In order to assess the antibacterial and antifungal behavior, the ligands and their metal(II) complexes were screened for their in vitro antibacterial activity against four Gram-negative species, Escherichia coli, Shigella flexneri, Pseudomonas aeruginosa and Salmonella typhi and two Gram-positive species, Staphylococcus aureus and Bacillus subtilis and, for in vitro antifungal activity against Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani and Candida glaberata. In vitro cytotoxic properties of all the compounds were also studied against Artemia salina by brine shrimp bioassay. The results of average antibacterial/antifungal activity showed that zinc(II) complexes were found to be the most active against one or more bacterial/fungal strains as compared to the other metal complexes.     

Anti-cowpox virus activities of certain adenosine analogs, arabinofuranosyl nucleosides, and 2'-fluoro-arabinofuranosyl nucleosides

Nucleoside analogs were investigated for their potential to inhibit cowpox virus (a surrogate for variola and monkeypox viruses) in cell culture and in lethal respiratory infections in mice. Cell culture antiviral activity was determined by plaque reduction assays, with cytotoxicity determined by cell proliferation assays. Selectivity indices (SI's, 50% cytotoxic concentration divided by 50% virus-inhibitory concentration) were determined for 15 compounds. Three arabinofuranosyl (Ara) nucleosides showed activity in mouse mammary tumor (C127I) cells: guanine (Ara-G), thymine (Ara-T), and adenine (Ara-A) with SI's of 113, 61, and 95, respectively. The 2'-fluoro-Ara nucleosides of 5-F-cytosine (FIAC), 5-methyluracil (FMAU), and 5-iodouracil (FIAU) exhibited SI's of 148, 77, and 29, respectively. Other potent compounds included cidofovir (a positive control) and 3'-O-methyladenosine, with SI values of 164 and 56, respectively. In general, assays performed in African green monkey kidney (Vero) cells produced lower SI's than in C127I cells, except for 5-iodo-2'-deoxyuridine (IDU) which had an SI of > 71 in Vero cells and 3.1 in C127I cells. Intranasal infection of mice with cowpox virus was followed a day later by twice daily intraperitoneal treatment with compounds for 5 days. Ara-A was active at 300 mg/kg/day (40% survival), FMAU at 100 mg/kg/day (70% survival), and cidofovir (given for 1 day only) at 100 mg/kg (80-100% survival). None of the other compounds, including IDU, prevented death nor delayed the time to death. Cidofovir had the best potential for treating orthopoxvirus infections of those tested.