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PubMed1992

Asymmetric synthesis of 1,3-dioxolane-pyrimidine nucleosides and their anti-HIV activity.

In order to study the structure-activity relationships of dioxolane nucleosides as potential anti-HIV agents, various enantiomerically pure dioxolane-pyrimidine nucleosides have been synthesized and evaluated against HIV-1 in human peripheral blood mononuclear cells. The enantiomerically pure key intermediate 8 has been synthesized in nine steps from 1,6-anhydro-D-mannose (1), which was condensed with 5-substituted pyrimidines to obtain various dioxolane-pyrimidine nucleosides. Upon evaluation of these compounds, cytosine derivative 19 was found to exhibit the most potent anti-HIV agent although it is the most toxic. The order of anti-HIV potency was as follows: cytosine (beta-isomer) greater than thymine greater than cytosine (alpha-isomer) greater than 5-chlorouracil greater than 5-bromouracil greater than 5-fluorouracil derivatives. Uracil, 5-methylcytosine, and 5-iodouracil derivatives were found to be inactive. Interestingly, alpha-isomer 20 showed good anti-HIV activity without cytotoxicity. As expected, other alpha-isomers did not exhibit any significant antiviral activity. (-)-Dioxolane-T was 5-fold less effective against AZT-resistant virus than AZT-sensitive virus.

Antiviral Agents↗
PubMed2000

In vitro selection of mutations in the human immunodeficiency virus type 1 reverse transcriptase that decrease susceptibility to (-)-beta-D-dioxolane-guanosine and suppress resistance to 3'-azido-3'-deoxythymidine.

Human immunodeficiency virus type 1 (HIV-1) isolates resistant to (-)-beta-D-dioxolane-guanosine (DXG), a potent and selective nucleoside analog HIV-1 reverse transcriptase (RT) inhibitor, were selected by serial passage of HIV-1(LAI) in increasing drug concentrations (maximum concentration, 30 microM). Two independent selection experiments were performed. Viral isolates for which the DXG median effective concentrations (EC(50)s) increased 7.3- and 12.2-fold were isolated after 13 and 14 passages, respectively. Cloning and DNA sequencing of the RT region from the first resistant isolate identified a K65R mutation (AAA to AGA) in 10 of 10 clones. The role of this mutation in DXG resistance was confirmed by site-specific mutagenesis of HIV-1(LAI). The K65R mutation also conferred greater than threefold cross-resistance to 2',3'-dideoxycytidine, 2', 3'-dideoxyinosine, 2',3'-dideoxy-3'-thiacytidine, 9-(2-phosphonylmethoxyethyl)adenine, 2-amino-6-chloropurine dioxolane, dioxolanyl-5-fluorocytosine, and diaminopurine dioxolane but had only marginal effects on 3'-azido-3'-deoxthymidine (AZT) susceptibility. However, when introduced into a genetic background for AZT resistance (D67N, K70R, T215Y, T219Q), the K65R mutation reversed the AZT resistance. DNA sequencing of RT clones derived from the second resistant isolate identified the L74V mutation, previously reported to cause ddI resistance. The L74V mutation also decreased the AZT resistance when the mutation was introduced into a genetic background for AZT resistance (D67N, K70R, T215Y, T219Q) but to a lesser degree than the K65R mutation did. These findings indicate that DXG and certain 2',3'-dideoxy compounds (e.g., ddI) can select for the same resistance mutations and thus may not be optimal for use in combination. However, the combination of AZT with DXG or its orally bioavailable prodrug (-)-beta-D-2, 6-diaminopurine-dioxolane should be explored because of the suppressive effects of the K65R and L74V mutations on AZT resistance.

Cells, Cultured↗
PubMed1992

The effect of maternal exposure to dioxolane on prenatal and postnatal development in rats.

Female rats were given by gavage every other day from days 8-20 of gestation an aqueous solution of dioxolane at daily doses equal to 0.025, 0.1 and 0.2 LD50 (first series--prenatal development) or from days 2-20 of gestation at daily doses equal to 0.025, 0.075 and 0.15 LD50 (second series--postnatal development). At doses toxic or subtoxic to maternal rats (0.1 and 0.2 LD50) dioxolane did not cause increased embryo or fetus intrauterine death rates or congenital defects, it did cause, however, dose-related delays in fetal development. Dioxolane does not cause impairment of physical development or behavioral disturbances. Exposure to higher doses of the compound (0.2 LD50) leads to increased perinatal death rates in the offspring, without causing, however, disturbances in the maternal instinct. The exposure of pregnant rats to dioxolane decreased haemoglobin levels in 5-week-old offspring. At a dose 1.15 g/kg (0.2 LD50) the chemical significantly increased exploratory motor activity of female offspring at the age of 8 weeks, but did not affect significantly locomotor activity of males and the active avoidance acquisition of adult offspring.

Animals↗
PubMed1987

[Experimental studies of toxic effects of 1,3,5-trioxane and 1,3-dioxolane. I. Acute toxic effect].

The problems arising from occupational exposure to 1,2,3-trioxane and 1,3-dioxolane made it necessary to carry out complex studies on that issue. This paper is focussed on systemic and local effects of those compounds. The studies involved: 1) Determination of acute systemic toxic effects following intragastric administration of the test compounds (DL50) and inhalatory exposure (CL50) using the Litchfield and Wilcoxon method as well as determination of medium lethal dose (MDLder) following dermal administration of the test compounds after Deichmann and Le Blanca, 2) Determination of the intensity of acute primarily irritating effects upon skin and eye using the Draize et al method, as well as irritating effects under repeated exposure, 3) Determination of allergic effects using the Magnusson and Kligman method, as modified by B. Krysiak. The DL50 and CL50 values for 1,3,5-trioxane and 1,3-dioxolane come to 8.5 g/kg m.c. and 5.8 g/kg m.c. respectively, and CL50 greater than 26000 mg/m3 and 87000 mg/m3 of air. Of those two compounds only 1,3-dioxolane may be absorbed through intact skin. However, the medium lethal dose MDLder coming to 15 g/kg b.w. in the rabbit implies that the rate of skin absorption for that compound is too low to induce a severe poisoning. Locally, the compounds exhibit irritating effects upon the eyeball and eye protective apparatus. As regards the irritating effectus upon skin, only 1,3-dioxolane induces skin irritation under repeated exposure. Under experimental conditions, no dermatitis related to oversensitivity was found.

Acute Disease↗
PubMed1984

[Mutagenic and gonadotoxic properties of trioxane and dioxolane].

The study was aimed at evaluation of the effects of trioxane and dioxolane on the fertility and frequency of dominant lethal mutations in germ cells of male rats. In the first experiment each test compound was administered per os at doses of 0,1 LD50 or 0,2 LD50 to male rats once a day, 5 days a week, throughout 8 weeks. During every week of treatment each male was mated with two females. In the second experiment, male rats exposed by inhalation 5 hours daily, 5 days a week, for 12 months, to trioxane or dioxolane at concentrations of 2500 mg/m3 were mated through one week with female rats in ratio 1:2. The autopsy of dams was carried out 13-14 days after the middle of mating intervals. No increase in the number of preimplantation losses, dead implants and alive fetuses per female was noted in any treated group as compared to an appropriate control group. The test noted in any treated group as compared to an appropriate control group. The test compounds did not affect the fertility of males, although in some rats treated with trioxane or dioxolane microscopic examination of testes revealed focal necrosis of seminiferous epithelium and alteration of spermatogenesis. The study did not reveal induced dominant lethal mutations in germ cells of male rats treated per os or by inhalation with trioxane or dioxolane.

Animals↗
PubMed1995

[Substrate properties of dioxolane analogs of 3'-deoxythymidine-5'-triphosphate in DNA synthesis reactions, catalyzed by various DNA polymerases].

The substrate properties of 3'-deoxythymidine 5'-triphosphate analogs prepared on the basis of 2,4-disubstituted 1,3-dioxolanes were investigated in reactions of the DNA synthesis catalyzed by various DNA polymerases. The 4'-triphosphates of (+/-)-cis-4-hydroxymethyl-2-(1-thyminylmethyl)-1,3-dioxolane and the corresponding (+/-)-trans-isomer were shown to be terminating substrates of terminal deoxynucleotidyl transferase. 4'-Triphosphate of (+/-)-cis-4-hydroxymethyl-2-(1-thyminylmethyl)- 1,3-dioxolane terminates the DNA synthesis catalyzed by HIV reverse transcriptase, whereas 2'-triphosphate of (+/-)-cis-2-hydromethyl-4-(1-thyminylmethyl)-1,3-dioxolane is a terminator in the DNA synthesis catalyzed by HIV reverse transcriptase and the Klenow fragment of DNA polymerase I.

Base Sequence↗
PubMed1994

Synthesis and antitumor activity of a series of [2-substituted-4,5-bis(aminomethyl)-1,3-dioxolane]platinum(II) complexes.

The synthesis, physical properties, antitumor activity, structure-activity relationships, and nephrotoxicity of a series of [2-substituted-4,5-bis(aminomethyl)-1,3-dioxolane]platinum(II) complexes are described. The 42 platinum(II) complexes having a seven-membered ring structure in this series have been prepared and characterized by 1H NMR, 13C NMR, IR, FAB-MS, and elemental analysis. All members of the series were designed to have a 1,3-dioxolane ring moiety in their carrier ligands to increase water solubility. The solubility of platinum complexes was related to the nature of leaving ligands and 2-substituents in the 4,5-bis(aminomethyl)-1,3-dioxolane carrier ligands. In general, compounds having two different R1 and R2 substituents in the 4,5-bis(aminomethyl)-1,3-dioxolane moiety were more water-soluble than those having the same substituents. Most members of this series showed the excellent antitumor activity against murine L1210 leukemia cells transplanted in mice and were superior to cisplatin and carboplatin. The (4R,5R)-stereoisomer 1a-h exhibited the higher antitumor activity than the corresponding (4S,5S)-stereoisomer 2a-h in the (1,1-cyclobutanedicarboxylato)platinum(II) complexes. The (glycolato)-platinum(II) complexes were highly cytotoxic toward four human stomach cancer cell lines, SNU-1, SNU-5, SNU-16, and NCI-N87, and among them, complexes 3d-g were even more cytotoxic than cisplatin. The (malonato)platinum(II) complex 1m and the (glycolato)platinum(II) complexes 3d-g were selected for further studies based on the greater in vivo and in vitro antitumor activity and desirable physical properties. The complexes 3e-g were almost equally cytotoxic to cisplatin toward human stomach cancer cell lines, KATO-III and MKN-45, and a human non-small cell lung cancer cell line, PC14. In contrast with cisplatin and carboplatin, five complexes selected significantly increased in life span in mice transplanted with cisplatin-resistant L1210 cells. Nephrotoxicity studies in ICR mice indicated that serum BUN and creatinine levels were not elevated when five complexes were given at a dose equal to 1.5 times the optimal dose determined in the in vivo L1210 screening system.

Animals↗
PubMed1997

Stereocontrol in Intermolecular Dirhodium(II)-Catalyzed Carbonyl Ylide Formation and Reactions. Dioxolanes and Dihydrofurans.

Ethyl diazoacetate undergoes dirhodium(II)-catalyzed reactions with aryl aldehydes to form 1,3-dioxolanes as mixtures of diastereoisomers in good yields. Carbonyl ylides are reaction intermediates. Catalyst dependent diastereocontrol is observed for reactions with p-nitrobenzaldehyde, but not for those with p-anisaldehyde or benzaldehyde, so that at least with transformations involving p-nitrobenzaldehyde a metal-stabilized ylide is responsible for product formation. Higher yields are obtained with catalysis by dirhodium(II) carboxamidates than with the carboxylates. Diastereoselectivity in 1,3-dioxolane formation that occurs through the "free" ylide can be effectively controlled so that only one diastereomer is produced through the use of 2,6-di-tert-butyl-4-methylphenyl diazoacetate (BDA) or dicyclohexylmethyl diazoacetate (DCM). The thermodynamically least stable all-cis trisubstituted 1,3-dioxolane is the primary product from p-nitrobenzaldehyde "cycloaddition" to the metal-stabilized ylide. Reactions that take place in the presence of p-anisaldehyde and dimethyl acetylenedicarboxylate (DMAD) result in the formation of one 2,5-dihydrofuran-2-carboxylate stereoisomer in good yield. In contrast, with p-nitrobenzaldehyde and DMAD both dihydrofuran stereoisomers are produced along with, mainly, the dioxolane derived from the metal-stabilized ylide; there is in this case competition between addition reactions of the "free" ylide and the metal-associated ylide.

Journal Article↗
PubMed2004

Surface tension and density of mixtures of 1,3-dioxolane+alkanols at 298.15 K: analysis under the extended Langmuir model.

Surface tensions (sigma) for [1,3-dioxolane+methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, and 1-pentanol] and excess molar volumes (v(E)) for [1,3-dioxolane+methanol, ethanol, 1-propanol, 2-propanol, and 2-butanol] at the temperature 298.15 K and normal atmospheric pressure have been determined as a function of mole fractions. The magnitude of these experimental quantities is discussed in terms of the nature and type of intermolecular interactions in binary mixtures. In order to analyze the surface tension behavior, the extended Langmuir (EL) model was used and the results obtained for the systems containing 1,3-dioxolane were compared with those of other formerly published series: [1,4-dioxane+alkanes] and [1,4-dioxane+alcohols].

Alcohols↗
PubMed1999

The conduction of protons in different stereoisomers of dioxolane-linked gramicidin A channels.

Two different stereoisomers of the dioxolane-linked gramicidin A (gA) channels were individually synthesized (the SS and RR dimers;. Science. 244:813-817). The structural differences between these dimers arise from different chiralities within the dioxolane linker. The SS dimer mimics the helicity and the inter- and intramolecular hydrogen bonding of the monomer-monomer association of gA's. In contrast, there is a significant disruption of the helicity and hydrogen bonding pattern of the ion channel in the RR dimer. Single ion channels formed by the SS and RR dimers in planar lipid bilayers have different proton transport properties. The lipid environment in which the different dimers are reconstituted also has significant effects on single-channel proton conductance (g(H)). g(H) in the SS dimer is about 2-4 times as large as in the RR. In phospholipid bilayers with 1 M [H(+)](bulk), the current-voltage (I-V) relationship of the SS dimer is sublinear. Under identical experimental conditions, the I-V plot of the RR dimer is supralinear (S-shaped). In glycerylmonooleate bilayers with 1 M [H(+)](bulk), both the SS and RR dimers have a supralinear I-V plot. Consistent with results previously published (. Biophys. J. 73:2489-2502), the SS dimer is stable in lipid bilayers and has fast closures. In contrast, the open state of the RR channel has closed states that can last a few seconds, and the channel eventually inactivates into a closed state in either phospholipid or glycerylmonooleate bilayers. It is concluded that the water dynamics inside the pore as related to proton wire transfer is significantly different in the RR and SS dimers. Different physical mechanisms that could account for this hypothesis are discussed. The gating of the synthetic gA dimers seems to depend on the conformation of the dioxolane link between gA's. The experimental results provide an important framework for a detailed investigation at the atomic level of proton conduction in different and relatively simple ion channel structures.

Biological Transport↗
PubMed2006

Imidazole-dioxolane compounds as isozyme-selective heme oxygenase inhibitors.

Several imidazole-dioxolane compounds were synthesized and evaluated as novel inhibitors of heme oxygenase (HO). These compounds, which include (2R,4R)-2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4-methyl-1,3-dioxolane (1) hydrochloride, are structurally distinct from metalloporphyrin HO inhibitors and lack the aminothiophenol moiety of azalanstat. They were found to be highly selective for the HO-1 isozyme (stress induced) and had substantially less inhibitory potency toward HO-2, the constitutive isozyme. These imidazole-dioxolane compounds are the first of their type known to exhibit this isozyme-selective HO inhibition.

Animals↗
PubMed2006

Asymmetric synthesis of 1,2-dioxolane-3-acetic acids: synthesis and configurational assignment of plakinic acid A.

The first asymmetric synthesis of 1,2-dioxolane-3-acetic acids is reported. Key features include the stereoselective opening of enantiomerically enriched oxetanes by hydrogen peroxide, conversion of the resulting 4-hydroperoxy-2-alkanols to 3-alkoxy-1,2-dioxolanes, and Lewis acid mediated homologation of the latter with a thioester silyl ketene acetal. The approach is modeled on 3,5-dimethyl-5-hexadecyl-1,2-dioxolane-3-acetic acid (1a), an unnamed natural product, and an optimized strategy is applied to the synthesis of four stereoisomers of plakinic acid A (2), allowing a configurational assignment of this incompletely characterized natural product.

Alcohols↗
PubMed2006

Selectivity of imidazole-dioxolane compounds for in vitro inhibition of microsomal haem oxygenase isoforms.

Haem oxygenases (HO) are involved in the catalytic breakdown of haem to generate carbon monoxide (CO), iron and biliverdin. It is widely accepted that products of haem catabolism are involved in biological signaling in many physiological processes. Conclusions to most studies in this field have gained support from the judicious use of synthetic metalloporphyrins such as chromium mesoporphyrin (CrMP) to selectively inhibit HO. However, metalloporphyrins have also been found to inhibit other haem-dependent enzymes, such as nitric oxide synthase (NOS), cytochromes P-450 (CYPs) and soluble guanylyl cyclase (sGC), induce the expression of HO-1 or exhibit varied toxic effects. To obviate some of these problems, we have been examining non-porphyrin HO inhibitors and the present study describes imidazole-dioxolane compounds with high selectivity for inhibition of HO-1 (rat spleen microsomes) compared to HO-2 (rat brain microsomes) in vitro. (2R,4R)-2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4-methyl-1,3-dioxolane hydrochloride) was identified as the most selective inhibitor with a concentration of 0.6 microM inhibiting HO-1(inducible) by 50% compared with 394 microM for HO-2 (constitutive). These compounds were found to have no effects on the catalytic activities of rat brain NOS and lung sGC, but were potent inhibitors of microsomal CYP2E1 and CYP3A1/3A2 activities. In conclusion, we have identified imidazole-dioxolanes that are able to inhibit microsomal HO in vitro with high selectivity for HO-1 compared to HO-2, and little or no effect on the activities of neuronal NOS and sGC. These molecules could be used to facilitate studies on the elucidation of physiological roles of HO/CO in biological systems.

Animals↗
PubMed2003

Dioxolane guanosine 5'-triphosphate, an alternative substrate inhibitor of wild-type and mutant HIV-1 reverse transcriptase. Steady state and pre-steady state kinetic analyses.

The frequency of human immunodeficiency virus, type 1 (HIV-1) mutations in response to antiviral therapy and resulting drug resistance is of major concern. Amdoxovir ((-)-beta-D-2,6-diaminopurine dioxolane), the prodrug of dioxolane guanosine (DXG), is currently in phase I/II clinical development for the treatment of HIV-1 infection. In vitro, HIV-1 mutants resistant to 3'-azido-3'-deoxythymidine (M41L/D67N/K70R/T215Y/K219Q) and (-)beta-L-2',3'-dideoxy-3'-thiacytidine (3TC) (M184V) remain sensitive to DXG. HIV-1 with the reverse transcriptase mutations K65R, L74V, and/or Q151M were less sensitive to DXG, whereas the mutation K103N re-sensitized the virus to the inhibitory effect of DXG. In order to understand these observations at the enzyme level, we investigated the inhibition of the HIV-1 reverse transcriptase-catalyzed viral DNA synthesis by dioxolane guanosine 5'-triphosphate (DXG-TP), 3'-azido-3'-deoxythymidine-TP, and 3TC-TP by using steady state kinetic analysis and the incorporation of DXG-5'-monophosphate by using pre-steady state kinetic analysis. This mechanistic study provided detailed information on the amdoxovir-related drug resistance at a molecular level. Overall, the enzymatic data correlated well with the antiviral data obtained from cell culture experiments and further supported the use of amdoxovir for the treatment of nucleoside reverse transcriptase inhibitor-experienced patients.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Electron impact mass spectral fragmentation of chiral bisbenzoxazole, bisbenzothiazole and biscarbamide derivatives of 2,2-dimethyl-1,3-dioxolane.

The mass spectrometric fragmentation behaviour of five pairs of (R,R)- and (S,S)-4,5-bis(benzoxazol-2-yl)-2,2-dimethyl-1,3-dioxolane derivatives, one pair of (R,R)- and (S,S)-4,5-bis(benzothiazol-2-yl)-2,2-dimethyl-1,3-dioxolanes, and three pairs of (R,R)- and (S,S)-N,N'-bis(2-hydroxyaryl)-2,2-dimethyl-1,3-dioxolane-4,5-dicarbamides, all important compounds for asymmetric catalysis (P. Jiao et al., Tetrahedron Asymmetry 2001; 12: 3081), has been studied with the aid of mass-analyzed ion kinetic energy spectrometry and accurate mass measurements under electron impact ionization conditions. The spectral observations have been rationalized in terms of fragment ion structures and fragmentation mechanisms that will provide an aid to spectral interpretation for new compounds of this type.

Journal Article↗
PubMed2006

Stereoselective one-pot synthesis of constrained N,O-orthogonally protected C-glycosyl norstatines [C(1')-aminoglycosyl-1,3-dioxolan-4-ones].

A procedure for the synthesis of conformationally constrained C-glycosyl norstatines has been developed. The key step of the reaction is the addition of (S)-N-sulfinyl azomethines to chiral (2S)-enolates of dioxolanones which exploits Seebach's "SRS" principle. The trisubstituted C-glycosyl-alpha-hydroxy-beta-amino acids are formed as N,O-orthogonally protected 1'-glycosyl-sulfinylamino-dioxolan-4-ones, usually with high diastereomeric excesses. Both the sulfinyl group at the nitrogen atom and the acetal moiety of the dioxolanone ring were selectively removed, thus demonstrating the orthogonality of the two protecting groups. In fact, the MeO(-) induced methanolysis of the acetal group gave the corresponding methyl C-glycosyl-sulfinylamino-isoserinates, while the acid induced removal of the sulfinyl group gave the Nu-deprotected 1'-glycosylamino-dioxolan-4-ones, which were in several cases subjected to a one-pot base-induced cyclization yielding the corresponding glycosyl-beta-lactams. This allowed the stereochemical configuration assessment of the parent 1'-glycosyl-sulfinylamino-dioxolan-4-ones by chemical correlation methods or by NOE experiments performed on the beta-lactams.

Aminocaproates↗
PubMed2000

Gating and permeation in ion channels formed by gramicidin A and its dioxolane-linked dimer in Na(+) and Cs(+) solutions.

The association of two gramicidin A (gA) peptides via H-bonds in lipid bilayers causes the formation of an ion channel that is selective for monovalent cations only. In this study, two gAs were covalently linked with a dioxolane group (SS dimer). Some functional properties of natural gA channels were compared to that synthetic dimer in Na(+)- or Cs(+)-containing solutions. The SS dimer remained in the open configuration most of the time, while natural gA channels had a relatively brief mean open time. Single channel conductances to Na(+) (g(Na)) or Cs(+) (g(Cs)) in the SS dimer were smaller than in natural gA. However, g(Na) was considerably more attenuated than g(Cs). This probably results from a tight solvation of Na(+) by the dioxolane linker in the SS channel. In Cs(+) solutions, the SS had frequent closures. By contrast, in Na(+) solutions the synthetic dimer remained essentially in the open state. The mean open times of SS channels in different solutions (T(open, Na) > T(open,Cs) > T(open,H)) were inversely proportional to the single channel conductances (g(H) > g(Cs) > g(Na)). This suggests that ion occupancy inside the pore stabilizes the open configuration of the gA dimer. The mean closed time of the SS dimer was longer in Cs(+) than in H(+) solutions. Possible mechanisms for these effects are discussed.

Cesium↗