Synthesis and complement inhibitory activity of B/C/D-ring analogues of the fungal metabolite 6,7-diformyl-3',4',4a',5',6',7',8',8a'-octahydro-4,6',7'-trihydroxy- 2',5',5',8a'-tetramethylspiro[1'(2'H)-naphthalene-2(3H)-benzofuran

This paper reports the synthesis and the bioassay of 4-methoxy- and 4-hydroxyspiro[benzofuran-2(3H)-cyclohexane] partial analogues (5) of the complement inhibitory sesquiterpene fungal metabolite 6,7-diformyl-3',4',4a',5',6',7',8',8a'-octahydro-4,6',7'-trihydroxy-2',5',5',8a'-tetramethylspiro[1'(2'H)-naphthalene-2(3H)-benzofuran] (1a, K-76) and its silver oxide oxidized product (1b, K-76COOH). The described target compounds represent spirobenzofuran B/C/D-ring analogues lacking the A-ring component of the prototype structure. The target compounds were evaluated by the inhibition of total hemolytic complement activity in human serum. It was observed that the structurally simplified analogue 4-methoxyspiro[benzofuran-2(3H)-cyclohexane]-6-carboxylic acid (5a) exhibited an IC(50) = 0.53 mM similar to the IC(50) = 0.57 mM that was observed for the natural product derivative 1b. Exhibiting an IC(50) = 0.16 mM, the three-ringed partial structure 6-carboxy-7-formyl-4-methoxyspiro[benzofuran-2(3H)-cyclohexane] (5k)was found to be the most potent target compound. Like the natural product, 5k appears to inhibit primarily at the C5 activation step and inhibits both the classical and alternative human complement pathways. Several other analogues inhibited complement activation in vitro at concentrations similar to those required for inhibition by the natural product 1b.     

Studies on enzyme-cleavable dialkoxymethyl-cyclosaligenyl-2',3'-dideoxy-2',3'-didehydrothymidine monophosphates

Recently we reported on conceptually new enzymatically activated cycloSal-pronucleotides. Now, we developed this concept further with new compounds of this type. The basic idea is fast intracellular cleavage of a functionalized group at the cycloSal residue that results in a rapid delivery of the nucleotide and thus an intracellular enrichment of the nucleotide. The introduction of a higher alkylated acylal group, the di- iso-butyryloxymethyl group, to the aromatic ring led to the expected higher stability of these prodrugs against enzymatic cleavage but also entailed surprisingly a decrease in hydrolysis stabilities and solubility problems. For some compounds, a separation of the two diastereomeric forms ( R P or S P) was achieved. By X-ray structure analysis, the absolute configuration at the P-atom was assigned. For all separated diastereomers the ( S P) form showed better antiviral activity than the ( R P) form.     

Asymmetric synthesis and antiviral activities of L-carbocyclic 2', 3'-didehydro-2',3'-dideoxy and 2',3'-dideoxy nucleosides.

Asymmetric syntheses of L-carbocyclic 2',3'-didehydro-2',3'-dideoxy- and 2',3'-dideoxypyrimidine and purine nucleoside analogues were accomplished, and their anti-HIV and anti-HBV activities were evaluated. The key intermediate, (1S, 4R)-1-benzoyloxy-4-(tert-butoxymethyl)cyclopent-2-ene (7), was prepared by benzoylation of the alcohol 2, selective deprotection of the isopropylidene group of 3, followed by thermal elimination via cyclic ortho ester or deoxygenation via cyclic thionocarbonate. The target compounds were also synthesized by thermal elimination via cyclic ortho esters from protected nucleosides. It was found that L-carbocyclic 2',3'-didehydro-2',3'-dideoxyadenosine (34) exhibited potent anti-HBV activity (EC(50) = 0.9 microM) and moderate anti-HIV activity (EC(50) = 2.4 microM) in vitro without cytotoxicity up to 100 microM.     

Metabolite of 2,2',4',5-tetrabromobiphenyl, 3-methylsulphonyl-2,2',4',5-tetrabromobiphenyl,a potent inducer of CYP2B1/2 in rat

1. 3-Methylsulphonyl- and 4-methylsulphonyl-2,2',4',5-tetrabromobiphenyls (3-MeSO(2)- and 4-MeSO(2)-TetraBrBs) were detected in the liver, lung, kidney, adipose tissue and faeces of the 2,2',4',5-tetrabromobiphenyl (TetraBrB)-dosed rat. 2. The administration of 0.05-2.0 micromol kg(-1) doses of 3-MeSO(2)-TetraBrB produced corrresponding increases in the hepatic concentration of the methyl sulphone metabolite, corresponding increases in the content of total cytochrome P450, and corresponding increases in the activities of 7-benzyloxy-, 7-ethoxy- and 7-pentoxyresorufin O-dealkylases. The inducing effects of the 3-MeSO(2)-TetraBrB (0.2 micromol kg(-1)), both on the content of total P450 and on the activities of the three alkoxyresorufin O-dealkylases, were higher than that of the parent TetraBrB (342 micromol kg(-1)). 3. The major phenobarbital (PB)-inducible forms of P450, CYP2B1, CYP2B2, CYP3A2 and CYP2C6, were substantially induced by 3-MeSO(2)-TetraBrB, but CYP1A1 and CYP1A2 were not. On the other hand, the activities of drug-metabolizing enzymes and the four PB-inducible forms of P450 were unchanged by 4-MeSO(2)-TetraBrB treatment. 4. The induction profiles of these enzymes and P450 forms in rat treated with 3-MeSO(2)-TetraBrB were similar to those treated with PB. 5. The inducing ability of 3-MeSO(2)-TetraBrB (0.5 micromol kg(-1)) both on the activities of the three alkoxyresorufin O-dealkylases and on the contents of four PB-inducible forms of P450 was roughly equal to that of PB (431 micromol kg(-1) twice at a 24-h interval) or 3-MeSO(2)-2,2',4',5-tetrachlorobiphenyl (1 micromol kg(-1)). It is noteworthy that the effects of 3-MeSO(2)-TetraBrB on the drug-metabolizing enzymes CYP2B1 and CYP2B2 were several thousand-fold higher than those of parent TetraBrB, while the effect of its isomeric 4-MeSO(2)-TetraBrB were not. 6. The extent of hepatic accumulation of the 3-MeSO(2) metabolite after the administration of TetraBrB (342 micromol kg(-1)) was almost the same as that after the administration of 3-MeSO(2)-TetraBrB (0.1-0.2 micromol kg(-1)). The relationship between the hepatic concentration of the 3-MeSO(2) metabolite and the extent of enzyme induction after the administration of TetraBrB or 3-MeSO(2)-TetraBrB suggests that 3-MeSO(2)-TetraBrB plays an important role in the induction of microsomal drug-metabolizing enzymes by TetraBrB.     

Stereoselective synthesis and antiviral activity of D-2',3'-didehydro-2',3'-dideoxy-2'-fluoro-4'-thionucleosides

As 2',3'-didehydro-2',3'-dideoxy-2'-fluoronucleosides have exhibited interesting antiviral effects against HIV-1 as well as HBV, it is of interest to synthesize the isosterically substituted 4'-thionucleosides in which 4'-oxygen is replaced by a sulfur atom. To study structure-activity relationships, various pyrimidine and purine nucleosides were synthesized from the key intermediate (2R,4S)-1-O-acetyl-5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-2-fluoro-2-phenylselenyl-4-thio-beta-D-ribofuranoside 8, which was prepared from the 2,3-O-isopropylidene-D-glyceraldehyde 1 in 13 steps. The antiviral activity of the synthesized compounds were evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells, among which cytidine 17, 5-fluorocytidine 18, adenosine 24, and 2-fluoroadenosine 32 showed moderate to potent anti-HIV activities (EC(50) 1.3, 11.6, 8.1, and 1.2 microM, respectively). It is noteworthy that 2-fluoroadenosine analogue 32 showed antiviral potency as well as high cytotoxicity (IC(50) 1.5, 1.1, and 7.6 microM for PBM, CEM, and Vero, respectively) whereas no other compound showed cytotoxicity up to 100 microM. The cytidine 17 and 5-fluorocytidine 18 analogues showed significantly decreased antiviral activity against the clinically important lamivudine-resistant variants (HIV-1(M184V)), whereas the corresponding D-2'-Fd4 nucleosides showed limited cross-resistance. Molecular modeling studies demonstrated that the larger van der Waals radius as well as the close proximity to Met184 of the 4'-sulfur atom of D-2'-F-4'-Sd4C (17) may be the reasons for the decreased antiviral potency of synthesized 4'-thio nucleosides against the lamivudine-resistant variants (HIV-1(M184V)).     

The anti-HTLV-III (anti-HIV) and cytotoxic activity of 2',3'-didehydro-2',3'-dideoxyribonucleosides: a comparison with their parental 2',3'-dideoxyribonucleosides

A series of 2',3'-didehydro-2',3'-dideoxyribonucleosides (ddeNs) [i.e., 2',3'-dideoxythymidinene (ddeThd), 2',3'-dideoxyuridinene (ddeUrd), 2',3'-dideoxycytidinene (ddeCyd), and 2',3'-dideoxyadenosinene (ddeAdo)] has been synthesized and the individual members compared in terms of their in vitro antiviral, antimetabolic, and cytostatic properties to their 2',3'-saturated counterparts (ddNs) (i.e., ddThd, ddUrd, ddCyd and ddAdo). All ddeNs except ddeUrd are potent and/or selective inhibitors of human immunodeficiency virus (HIV) in vitro, ddeCyd being the most potent (MIC50, 0.30 microM). The inhibitory effect of ddeCyd on ATH8 cell proliferation and HIV-induced cytopathogenicity is comparable to that of ddCyd. ddeThd is a more potent anti-HIV agent than ddThd (MIC50, 3.4 microM and 84 microM, respectively), but also more cytostatic (ID50, 172 microM and greater than 2000 microM, respectively). However, its in vitro chemotherapeutic index is higher than that of 3'-azido-2',3'-dideoxythymidine, a drug which has recently proven effective in the treatment of acquired immunodeficiency syndrome. ddeAdo has a weaker anti-HIV and a stronger cytostatic effect than ddAdo. Neither ddeUrd nor ddUrd shows significant anti-retroviral activity at 500 microM. In contrast to their anti-retroviral activity, both ddNs and ddeNs lack any appreciable inhibitory activity against a series of nononcogenic RNA and DNA viruses, pointing to their selectivity as anti-retroviral agents. All ddeNs show a progressive loss of anti-retroviral effect upon prolonged incubation with virus-infected cells. This phenomenon is most likely due to the chemical instability of these compounds, and not to a preferential enzymatic phosphorolytic cleavage of the ddeNs. Evidence is presented that ddeCyd and ddCyd, and ddeThd and ddThd are phosphorylated by cellular dCyd kinase and dThd kinase, respectively. However, the Ki values as alternate substrate inhibitors for their respective kinases are high (greater than 500 microM), indicating poor substrate activity and, thus, poor anabolism in ATH8 cells.     

2'-Fluoro-2',3'-dideoxyarabinosyladenine: a metabolically stable analogue of the antiretroviral agent 2',3'-dideoxyadenosine

In this report, we have compared the uptake, metabolism, and relevant enzymology of a novel anti-acquired immunodeficiency syndrome drug, 2'-fluoro-2',3'-dideoxyarabinosyladenine (2'-F-dd-ara-A) with the corresponding properties of its parent compound 2',3'-dideoxyadenosine (2',3'-ddAdo) in three human T cell lines, MOLT-4, ATH8, and CEM. In previous communications, we have reported that the primary route of metabolism of 2',3'-ddAdo in human T lymphoblasts is catabolic, i.e., deamination to 2',3'-dideoxyinosine (2',3'-ddlno). At this point, the metabolic pathway diverges, to result in either cleavage and inactivation of 2',3'-ddlno by purine nucleoside phosphorylase or in 5'-phosphorylation by a phosphotransferase, a reaction that generates 2',3'-inosine monophosphate and ultimately the putative active metabolite 2',3'-dideoxy-ATP. Studies with kinase-deficient mutant CEM lines indicate, however, that 2'-F-dd-ara-A favors a more direct anabolic route toward formation of 2'-fluoro-dideoxynucleotides, catalyzed initially by 2'-deoxycytidine kinase. In MOLT-4 cells, amounts of 2'-fluoro-dideoxyarabinosyladenine di- and triphosphate formed were approximately 20-fold and 5-fold greater than the respective accumulation of 2',3'-dideoxy-ADP and 2',3'-dideoxy-ATP over the same time of exposure. This metabolic profile was supported by enzymological studies, which revealed that 2'-F-dd-ara-A is deaminated 10 times less rapidly than ddAdo and that the resulting deaminated product is resistant to hydrolysis by purine nucleoside phosphorylase. Under similar conditions, ddAdo was rapidly degraded through cleavage of its deamination product ddlno. Like ddAdo, 2'-F-dd-ara-A was found to be transported by passive diffusion and does not enter cells via the purine nucleoside transport carrier system. However, the rate of entry of 2'-F-dd-ara-A was about half that of ddAdo (9.7 pmol/10(6) cells/min for 2'-F-dd-ara-A versus 18.4 pmol/10(6) cells/min for ddAdo). This investigation, therefore, demonstrates that, under the conditions studied, 2'-F-dd-ara-A and its deamination product 2'-fluoro-2',3'-dideoxyarabinosylhypoxanthine have metabolic properties that differ significantly from those of their parent compounds ddAdo and ddlno. These properties, combined with the previously reported resistance of the fluorinated nucleosides to acid degradation, make these compounds interesting candidates for further study as orally administered agents for the inhibition of human immunodeficiency virus replication in patients with acquired immunodeficiency syndrome.     

cycloSal-Pronucleotides of 2',3'-dideoxyadenosine and 2', 3'-dideoxy-2',3'-didehydroadenosine: synthesis and antiviral evaluation of a highly efficient nucleotide delivery system

The synthesis, hydrolysis, and antiviral evaluation of novel, lipophilic cycloSal-ddAMP (9a-d) and cycloSal-d4AMP (10a-d) derivatives of the antiviral purine dideoxynucleoside analogues 2', 3'-dideoxyadenosine (ddA) (2) and 2',3'-dideoxy-2', 3'-didehydroadenosine (d4A) (3) are reported. These potential pronucleotides release ddAMP (7) or d4AMP (8) selectively by a controlled, chemically induced tandem reaction. All new compounds 9 and 10a-d were synthesized in good yields using our previously reported phosphorus(III) method starting from substituted salicyl alcohols 14a-h. The phosphotriesters 9 and 10 were obtained with a stereochemical preference of 2:1 with respect to the configuration at the phosphorus center. In an 1-octanol/water mixture phosphotriesters 9 and 10 exhibited 7-43-fold higher lipophilicity than the parent nucleosides ddA (2) and d4A (3) as judged by their log P values. In hydrolysis studies, 9 and 10 decomposed under mild aqueous basic conditions releasing solely ddAMP (7) and d4AMP (8), as well as the diols 14. Further hydrolysis studies under acidic conditions showed a marked increase in stability with respect to the acid-catalyzed cleavage of the glycosyl bond. Phosphotriesters 9 and 10 exhibited antiviral potencies against wild-type HIV-1 and HIV-2 strains in human T-lymphocyte (CEM/O) cells that were, respectively, 100- and 600-fold higher than those of ddA (2) and d4A (3). Furthermore, all triesters 9 and 10 were markedly more active than the corresponding ddI compounds 11 and 12, which supports the concept of the delivery of the adenine nucleotides. Studies with adenosine deaminase (ADA) and adenosine monophosphate deaminase (AMPDA) showed that the triesters were not substrates for enzymatic deamination. The studies reported herein demonstrate conclusively that the cycloSal triesters deliver exclusively the nucleotides ddAMP and d4AMP, not only under chemical-simulated hydrolysis but also under intracellular conditions fulfilling the adenosine deaminase bypass premise.     

Synthesis and anti-HIV activity of some novel arylphosphate and H-phosphonate derivatives of 3'-azido-2',3'-dideoxythymidine and 2',3'-didehydro-2',3'-dideoxythymidine.

Phosphate and H-phosphonate derivatives of anti-HIV nucleoside analogues (AZT and d4T) were prepared as potential prodrugs of the bio-active free nucleotide and they were evaluated for their inhibitory effects on the replication of HIV-1 in several cell culture systems. One compound exhibited an important anti-HIV-1 activity and proved to be significantly more efficient than the parent nucleoside.     

Effects of oral erythrosine (2',4',5',7'-tetraiodofluorescein) on the pituitary-thyroid axis in rats

Erythrosine (FD&C Red Dye No.3) is a tetraiodinated derivative of fluorescein. Rats fed a 4% erythrosine diet for 30 months beginning in utero have an increased incidence of thyroid adenomas and adenocarcinomas. These tumors may be secondary to increased stimulation of the thyroid gland by TSH. This study was undertaken to determine if dietary erythrosine disrupts the pituitary-thyroid axis thereby altering serum thyroid hormone levels. TSH levels, or the pituitary's response to TRH. Rats were fed diets containing erythrosine (0.5, 1.0, 4.0%), sodium iodide (0.16%), or fluorescein (1.6%) for 3 weeks after which TRH testing was performed in vivo. Erythrosine produced a dose-dependent increase in serum T4 levels. With the 4% erythrosine diet, serum T4 and T3 levels and the free-T4 index were significantly increased, whereas the free-T3 index were significantly increased, whereas the free-T3 index was unchanged. Rats fed the 4.0% erythrosine diet had an exaggerated TSH response to TRH; 10 min after the TRH injection, serum TSH levels were 80% greater than TSH levels of control rats. Short-term administration of erythrosine to rats decreased hepatic T3 production by decreasing its conversion of T4 to T3, indicating that erythrosine decreases hepatic 5'-deiodinase activity. These data demonstrate that dietary ingestion of 4% erythrosine disrupts the pituitary-thyroid axis as evidenced by an increased TSH response to TRH. This effect is mediated by erythrosine or an iodinated metabolite, since ingestion of its fluorescein nucleus had no effect. Erythrosine's effects were not likely mediated by iodide, because serum T4 and T3 levels were elevated and iodide administration did not increase the TSH response to TRH. These data suggest that erythrosine increases the pituitary's TSH response to TRH by altering thyrotroph cell conversion of T4 to T3. Chronic erythrosine ingestion may promote thyroid tumor formation in rats via chronic stimulation of the thyroid by TSH.     

Synthesis and antiretrovirus properties of 5'-isocyano-5'-deoxythymidine, 5'-isocyano-2',5'-dideoxyuridine, 3'-azido-5'-isocyano-3',5'-dideoxythymidine, and 3'-azido-5'-isocyano-2',3',5'-trideoxyuridine

The 5'-azidonucleosides 3 and 4 were obtained by treating thymidine and 2'-deoxyuridine with TPP/DEAD/HN3. The 3'-O-silylated 5'-azido-5'-deoxythymidine 5 and the corresponding 2'-deoxyuridine derivative 6 were transformed to the formamides (7 and 8, respectively) and dehydrated to the protected 5'-isocyano derivatives 9 and 10; deblocking gave 5'-isocyano-5'-deoxythymidine (11) and 5'-isocyano-2',5'-dideoxyuridine (12). 2,3'-Anhydro-5'-formamido derivatives of thymidine and 2'-deoxyuridine (19 and 20, respectively) were prepared by three different ways. In the most direct synthesis 3 and 4 were transformed to the 2,3'-anhydro-5'- azidonucleosides 17 and 18 by using TPP/DEAD; following the reaction with TPP/HCO2COCH3 gave 19 and 20. Nucleophilic opening reaction with LiN3 yielded the 3'-azido-5'-formylamino derivatives 21 and 22. Dehydration to 3'-azido-5'-isocyano-3',5'-dideoxythymidine (23) and 3'-azido-5'-isocyano-2',3',5'-trideoxyuridine (24) was achieved with tosyl chloride/pyridine. In contrast with 3'-azido-3'-deoxythymidine, compounds 11, 12, 23, and 24 were devoid of any marked inhibitory effect against DNA and RNA viruses including human immunodeficiency virus type I (HIV).     

Potential prodrug derivatives of 2',3'-didehydro-2',3'-dideoxynucleosides. Preparations and antiviral activities.

The preparations and antiviral activities of a series (4-17) of potential prodrug forms of the antivirals 2',3'-didehydro-2',3'-dideoxyadenosine (D4A) and 2',3'-didehydro-2',3'-dideoxycytosine (D4C) are reported. The 5'-phenyl- and 5'-methylphosphonates (4, 6, 8, and 10) and their phosphonothionate congeners (5, 7, 9, and 11), with the exception of 10, were inactive in vitro against HIV-1 and HIV-2. However, the 5'-phenyl, 5'-methyl, and 5'-(3'-thymidyl) phosphate diesters (12-17) demonstrated inhibition of the cytopathic effect of HIV-1 and HIV-2 (EC50 approximately 1-60 microM) and cytotoxicities (CC50 approximately 35-200 microM) at concentration levels comparable to those of their parent compounds, D4A and D4C. This strongly suggests that the diesters are hydrolyzed to the nucleosides D4A and D4C and/or their 5'-monophosphates. The facile hydrolysis of 12 and 13 to these products was demonstrated in a medium containing 10% fetal calf serum. The molecules can serve as ready prodrug sources of the free nucleosides and their 5'-monophosphates. Evidently, the phosphonates and phosphonothionates are not similarly cleaved, nor are they phosphorylated to form antivirally active or cytotoxic products. The importance of intracellular formation of these products in the activation of 12-17 is less clear. Potential prodrugs 4-17 are all stable in aqueous solution for hours with the exception of 14. Conjugates 4-17 showed no activity against a series of DNA and RNA viruses.     

Effects of oral erythrosine (2',4',5',7'-tetraiodofluorescein) on thyroid function in normal men

Erythrosine (Er), a tetraiodinated derivative of fluorescein, is a coloring agent widely used in foods, cosmetics, and pharmaceutical products. Because of its high iodine content and previous reports demonstrating an inhibitory effect of erythrosine on hepatic 5'-monodeiodination, we studied the effects of this compound on thyroid function and serum and urinary iodide concentrations in normal subjects. Thirty normal men, equally divided into three treatment groups, each received a 14-day course of oral Er in doses of 20, 60, or 200 mg/day. Serum thyroxine (T4), triiodothyronine (T3), reverse T3 (rT3), thyroid stimulating hormone (TSH), protein-bound iodide (PBI), and total iodide concentrations, serum T3-charcoal uptake, and 24-hour urinary iodide excretion were measured on Days 1, 8, and 15. Thyrotropin-releasing hormone (TRH) tests were performed on Days 1 and 15. There were no significant changes in serum T4, T3, rT3, and T3-charcoal uptake values at any dose. In men receiving 200 mg Er/day, the mean basal serum TSH concentration increased significantly from 1.7 +/- 0.1 (SE) on Day 1 to 2.2 +/- 0.1 microU/ml on Day 15 (p less than 0.05), and the mean peak TSH increment after TRH increased from 6.3 +/- 0.5 to 10.5 +/- 1.0 microU/ml (p less than 0.05). There were no significant changes in basal or peak TSH responses in the men receiving 20 or 60 mg Er/day. Significant dose-related increases in serum total iodide and PBI concentrations occurred during all three doses, and significant dose-related increases in urinary iodide excretion occurred during the 60 and 200 mg/day Er doses. These data suggest that the increase in TSH secretion induced by Er was related to the antithyroid effect of increased serum iodide concentrations, rather than a direct effect of Er on thyroid hormone secretion or peripheral metabolism.     

Synthesis and anti-HIV activity of carbocyclic 2',3'-didehydro-2',3'-dideoxy 2,6-disubstituted purine nucleosides

(+-)-cis-[4-[(2,5-Diamino-6-chloropyrimidinyl)amino]-2- cyclopentenyl]carbinol (5a) was synthesized from 2-amino-4,6-dichloropyrimidine and cis-4-(hydroxymethyl)cyclopentenylamine (2a) by subsequent preparation of the 5-[(4-chlorophenyl)azo] derivative of the resulting pyrimidine (3a) and reduction of the azo moiety with zinc and acetic acid. The carbocyclic analogue of 2',3'-didehydro-2',3'-dideoxy 2-amino-6-chloropurine (6a) and the corresponding 8-azapurine (9a) were prepared from 5a. The carbocyclic 2',3'-didehydro-2',3'-dideoxy analogues of guanine (7a) and 2,6-diaminopurine (8a), and 8-azaguanine (10a) and 8-aza-2,6-diaminopurine (11a) were prepared from 6a and 9a, respectively. The corresponding 2',3'-saturated series of 2-amino-6-substituted-purine carbocyclic nucleosides was prepared following the same scheme starting with cis-4-(hydroxymethyl)cyclopentylamine (2b). Carbocyclic 2',3'-didehydro-2',3'-dideoxyguanosine (carbovir, 7a) emerged as a potent and selective anti-HIV agent. Its hydrolytic stability and its ability to inhibit the infectivity and replication of HIV in T-cells at concentrations of approximately 200-400-fold below toxic concentrations make carbovir an excellent candidate for development as a potential antiretroviral agent.     

Conformational analysis of 2-hydroxy-2',5'-diazachalcones

Spatial arrangement of 2-hydroxy-2',5'-diazachalcones was studied by means of infrared and NMR spectral data and molecular models calculations. The models were calculated in vacuum using semi-empirical AM1 method (software HyperChem 5.1). The initial geometries of the molecules were built by means of standard parameters and then optimized by Polak-Ribiere geometrical optimization. It was found that (E)-s-cis-conformers with synperiplanar arrangement of C-alpha and C-6 have the lowest heats of formation (standard heat of formation).