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PubMed1978

Synthesis and pharmacological evaluation of a clofibrate-related tricyclic spirolactone, 5-chloro-4',5-dihydrospiro[benzofuran-2(3H),3'(2'H)-furan]-2'-one.

The chemistry and pharmacology of the title compound, spirolactone 4, are reported. The synthesis represents a new approach to the preparation of spiro compounds. The pharmacological profiles of 4 are compared to that of clofibrate in Triton-induced hyperlipidemic, sucrose-fed, and normal Sprague-Dawley rat models. Clofibrate was effective in all animal models, but the spirolactone 4 exhibited antitriglyceridemic activity only in the Triton model. The inactivity of 4 in sucrose- and chow-fed rats could not be attributed to a resistance to hydrolysis by serum esterases. Comparative studies revealed that inhibition of hepatic HMG-CoA reductase activity may not be an index of hypocholesterolemic action in sucrose-fed rats. Additionally, only clofibrate exhibited significant changes in components of the hepatic microsomal monooxygenase system.

Animals↗
PubMed1994

Synthetic and oxidative studies on 8-(arylamino)-2'-deoxyguanosine and -guanosine derivatives.

Facile aerial oxidation is a general feature of guanine ribo- and 2'-deoxyribonucleosides that are substituted at the 8-position by an aminoaryl group. In previous work, it had been suggested that two of the major oxidation products are a pair of diastereomers having a spiro structure. These were presumed to be related by a chiral difference at the spiro carbon atom. The pattern of the oxidative process involves a contraction of the pyrimidine ring. It was thought to be analogous to that suggested by other investigators for the oxidation of uric acid, but for which no really definitive evidence had been presented. We have been able now to isolate in a crystalline state one of the diastereomers produced by the aerial oxidation of 8-phenylaminoguanosine under alkaline conditions. Analysis by X-ray diffraction has now confirmed the type of spiro structure promulgated previously. These findings also imply that spiro compounds are likely to be produced during the aerial oxidation of any 8-arylaminoguanine nucleoside or 2'-deoxynucleoside. In addition, this work adds considerable weight to the results of Poje and Sokolic-Maravic who proposed that a spiro intermediate is produced during the aerial oxidation of uric acid (12,13). However, they found this compound to be unstable to base, in contrast to the arylaminoguanine oxidation products. In the course of the above work we showed that the 8-arylamino derivatives of guanosine can be converted by the Barton deoxygenation method to the corresponding 2'-deoxyribonucleosides. This makes available a number of the latter compounds, which are not easily prepared by other methods.

DNA Adducts↗
PubMed2003

1H,13C 2D NMR and X-ray studies of the products of the reaction between dibenzylidencyclohexanone and 6-amino-1,3-dimethyl uracil.

The reaction of the 6-amino-1,3-dimethyl uracil with the dibenzylidencyclohexanone (1), provided three adducts whose structures result from nucleophilic attack yielding the monoadduct 3 and two isomeric bisadducts (4 and 5) in moderate yields (50-60%). The structures obtained in this study were elucidated with 2D high resolution NMR experiments, variable temperature NMR and X-ray crystallographic studies. In compound 3, the tricyclic skeleton is essentially planar and the cyclohexane ring addopts an envelope conformation. The structures 4 and 5 correspond to two isomeric spiro compounds.

Crystallography, X-Ray↗
PubMedDate not supplied

Behaviour of 2-substituted 1,3-indandiones towards aldimines.

Treatment of 2-cyano-1,3-indandione (1) with aldimines gave the expected Mannich bases (2-4), while the arylidenes (7,8) were obtained when 2-ethoxycarbonyl-1,3-indandione (5) was subjected to react with aldimines. On the other hand, treatment of 2-acetyl-1,3-indandione (9) with aldimines gave compounds (11,12,14). The reaction of 2-phenyl-1,3-indandione (15) with aldimines gave the arylamino and the ethylene diamino derivatives (17, 18). Pictet Spengler reaction of 19b gave the spiro compound (21).

Imines↗
PubMed1996

Monoclonal antibody based enzyme immunoassay for marihuana (cannabinoid) compounds.

MAb against delta 1-THCA was produced by fusing hybridoma with splenocytes immunized with delta 1-THCA-BSA conjugate and hypoxanthine, aminopterine, thymidine-sensitive mouse myeloma cell line, P3-X63-Ag8-653. The cross-reaction of anti-delta 1-THCA antibody against other cannabinoids was very wide, thus many cannabinoids and a spiro-compound were reactive suggesting that 2'-hydroxyl, 6'-hydroxyl or 6'-O-alkyl, 4'-alkylbenzene ring moiety is necessary for its reactivity. It became evident that this ELISA was able to be applied to the biotransformation experiments of cannabinoids in plant tissue culture system. The metabolites of delta 6-THC such as two major metabolites, 7-oxo-delta 6-THC and 7-hydroxyl-delta 6-THC were also detectable by this ELISA.

Animals↗
PubMed2003

Novel preparation of 2,1-benzothiazine derivatives from sulfonamides with [hydroxy(tosyloxy)iodo]arenes.

Cyclization of sulfonamides bearing an aromatic ring at the beta-position with various organohypervalent iodine compounds was carried out to form the corresponding 2,1-benzothiazine derivatives. Among them, the cyclization effectively proceeded with [hydroxy(tosyloxy)iodo]arenes through ionic pathways. The same treatment of a sulfonamide bearing a 4-methoxyphenyl group at the beta-position generated a spiro compound.

Journal Article↗
PubMed1995

Synthesis of enantio-manoyl oxides: modifiers of the activity of adenylatecyclase enzyme.

Cyclization of methyl ent-8 alpha-hydroxylabd-13(16),14-dien-18-oate with m-chloroperbenzoic acid gave methyl (13S)-ent-16-hydroxy-8 alpha,13-epoxylabd-14-en-18-oate and its epimer at C-13. Biotransformation of the former (which exhibits antileishmania activity) with Rhizopus nigricans cultures produced the methyl (13S)-ent-11 beta,16-dihydroxy-8 alpha,13-epoxilabd-14-en-18-oate (carbomanoyl, which inhibits the activity of the adenylatecyclase enzyme), methyl (13S)-ent-3 beta,16-dihydroxy-8 alpha,13-epoxilabd-14-en-18-oate, methyl (13S)-ent-3 beta,11 beta,16-trihydroxy-8 alpha,13-epoxilabd-14-en-18-oate and the (14S)-ent-3 beta-hydroxy-14,15-epoxy derivative that cyclized spontaneously to a spiran compound. Biotransformation of methyl (13S)-ent-16-hydroxy-3-oxo-8 alpha,13-epoxilabd-14-en-18-oate with R. nigricans produced ent-11 beta-hydroxylation, reduction of the keto group at C-3 (to give 3S-alcohol) and 14(S),15-epoxidation, which also rearranged to a spiro compound.

Adenylyl Cyclase Inhibitors↗
PubMedDate not supplied

Simple synthesis of condensed pyran containing compounds and their antimicrobial properties.

Reaction of various fused pyran compounds with formic acid was studied. Thus, refluxing 6-aminopyrano[2,3-c]pyrazole-5-carbonitriles 3 with formic acid afforded the corresponding 3-aryl-3-(5-hydroxy-3-methyl-1H-pyrazole-4-yl)propanoic acids 4. Whereas, reaction of formic acid with 2-amino-4H-1-benzopyran-3-carbonitriles 6 gave the corresponding quinoline-2,5(1H,6H)-diones 7. The study was also extended towards many spiro compounds possessing pyran residue. The antimicrobial properties of the prepared compounds was screened.

Anti-Bacterial Agents↗
PubMed2005

Silicon chelation in aqueous and nonaqueous media: the furanoidic diol approach.

Anhydroerythritol (AnEryt) shares some of its ligand properties with furanosides and furanoses. Its bonding to silicon centers of coordination number four, five, and six was studied by X-ray and NMR methods, and compared to silicon bonding of related compounds. Diphenyl(cycloalkylenedioxy)silanes show various degrees of oligomerization depending on the diol component involved. For example, Ph(2)Si(cis-ChxdH(-2)) (1) and Ph(2)Si[(R,R)-trans-ChxdH(-2))] (2; Chxd = cyclohexanediol) are dimeric, Ph(2)Si(AnErytH(-2)) (3) is monomeric, and Ph(2)Si(L-AnThreH(-2)) (4; AnThre = anhydrothreitol) is trimeric both in the solid state and in solution. Ph(2)Si(cis-CptdH(-2)) (5) (Cptd = cyclopentanediol) is monomeric in solution but dimerizes on crystallization. Si(AnErytH(-2))(2) (6) and Si(cis-CptdH(-2))(2) (7) are monomeric spiro compounds in solution but are pentacoordinate dimers in the crystalline state. Pentacoordinate silicate ions are found in A[Si(OH)(AnErytH(-2))(2)] (A = Na, 8 a; Rb, 8 b; Cs, 8 c). Related compounds are formed by substitution of the hydroxo by a phenyl ligand. K[SiPh(AnErytH(-2))(2)]1/2 MeOH (9) is a prototypical example as it shows the two most significant isomers in one crystal structure: the syn/anti and the anti/anti form (syn and anti define the oxolane ring orientation close to, or apart from, the monodentate ligand, respectively). syn/anti Isomerism generally rules the appearance of the NMR spectra of pentacoordinate silicates of furanos(id)e ligands. NMR spectroscopic data are presented for various pentacoordinate bis(diolato)silicates of adenosine, cytidine, methyl-beta-D-ribofuranoside, and ribose. In even more basic solutions, hexacoordinate silicates are enriched. Preliminary X-ray analyses are presented for Cs(2)[Si(CydH(-2))(3)] 21.5 H(2)O (10) and Cs(2)[Si(cis-InsH(-3))] cis-Ins8 H(2)O (11) (Cyd = cytidine, Ins = inositol).

Journal Article↗
PubMed2003

Preparation, structure, and unique thermal [2+2], [4+2], and [3+2] cycloaddition reactions of 4-vinylideneoxazolidin-2-one.

The terminal allene C(alpha)=C(beta) bonds of 4vinylidene-2-oxazolidinone (2) readily undergo [2+2] cycloaddition with a wide variety of terminal alkynes, alkenes, and 1,3-dienes irrespective of their electronic nature under strictly thermal activation conditions (70-100 degrees C) and provide 3substituted (Z)-methylenecyclobutenes 6, 3substituted methylenecyclobutanes 7 and 8, and 3vinylmethylenecyclobutanes 9, respectively, in good to excellent yields. Alkenes react with 2 with complete retention of configuration. The [2+2] cycloaddition is concluded to proceed via a concerted [(pi(2s)+pi(2s))(allene) + pi(2s)] Hückel transition state on the basis of experimental evidences and quantum mechanical methods. Some highly polarized enones and nitrile oxide, on the other hand, react with 2 selectively at the internal C(4)=C(alpha) double bonds and give spiro compounds 10 and 11, respectively. The bent allene bonds (173-176 degrees) and the unique reactivity associated with 2 are attributed to a low-lying LUMO (C(alpha)=C(beta)) that is substantiated by a through-space sigma*(N-SO(2))-pi*(C(alpha)=C(beta)) orbital interaction.

Journal Article↗
PubMed1989

A phase II study of spirogermanium in patients with advanced malignant lymphoma.

Spirogermanium was given as a 90 minute infusion to 47 eligible patients with refractory Hodgkin's (9 patients) or non-Hodgkin's lymphoma (38 patients). The schedule was 80 mg/m2 three times a week for the first two weeks and 100 mg/m2, 3 times a week, for the two subsequent weeks. In case of response or stable disease, the treatment was continued with biweekly infusions of 100 mg/m2 until tumor progression. In 64% of cases, three or more combinations had been previously administered; 66% of patients presented an extra-lymphatic spread of disease. Two patients with Hodgkin's disease showed a partial response of 11 and 23 weeks and two patients with non-Hodgkin's lymphoma achieved a complete response of 12 and 24 weeks. Overall, 14 patients showed a tumor progression within the first month of treatment. The main toxicity was neurological, with dizziness and lethargy during the infusion in 50% of cases. Hematologic toxicity was almost absent. Spirogermanium is ineffective in heavily pretreated patients with non-Hodgkin's lymphoma. The confirmed lack of activity in patients with refractory malignant lymphoma and the need of repeated and prolonged infusions definitely discourage the clinical use of the drug.

Adult↗
PubMed1989

Phase II trial of spirogermanium in advanced non-small cell lung cancer. An Illinois Cancer Council Study.

A phase II trial of spirogermanium was conducted in advanced previously untreated non-small cell lung cancer patients. The drug was given by intravenous infusion 3 times per week for 2 weeks, twice per week for the next 2 weeks, and then weekly. Starting dose was 125 mg/m2, and dose escalation of 25 mg/m2 per week was required in the absence of toxicity to a maximum dose of 200 mg/m2 per infusion. Fifteen eligible patients were treated, and no objective responses were seen. Primary toxicity was neurologic and reversible after withdrawal of the drug. We conclude that spirogermanium is not active against non-small cell lung cancer in the dosage used in this study.

Adult↗
PubMed1986

Spirogermanium--a novel antitumour agent expressing a lack of cross-resistance in vitro with a range of 'standard' antitumour drugs.

We have used a series of drug resistant continuous tumour cell lines of murine, hamster or human origin, to screen in vitro for new drugs effective at overcoming resistance expressed to clinically useful antitumour drugs. We have established that spirogermanium appears to express a unique lack of cross resistance to a wide range of 'standard' antitumour drugs including 5-fluorouracil, cisplatin, methotrexate, vincristine and adriamycin, as judged by its equivalent effectiveness in reducing survival, measured by clonogenic assays, of the parental and drug-resistant sublines following 24 hour in vitro treatments. Spirogermanium was also able to overcome the multidrug resistance exhibited by the colchicine-resistant mutant CHRC5 cells and a subline of vincristine-resistant MCF-7 human breast carcinoma cells, following 1 or 24 hour drug treatments. These preclinical studies suggest that this novel compound may prove a potentially useful agent for inclusion in 'non-cross-resistant drug combinations'.

Animals↗
PubMed1984

Identification of synergistic combinations of spirogermanium with 5-fluorouracil or cisplatin using a range of human tumour cell lines in vitro.

A series of continuous human tumour cell lines, derived from various tumour types, were used to establish whether the combination of spirogermanium (SP) with other 'standard' antitumour drugs proved superior to these as single agents in reducing cell survival in vitro. A non-cytotoxic concentration of SP was selected and when combined with a range of concentrations of cisplatin or 5-fluorouracil (5-FU), definite synergistic cell kill was noted in all lines tested. In contrast, the combination of SP with various other antitumor drugs, including adriamycin, methotrexate and the vinca alkaloids and with X-irradiation did not enhance cytotoxicity. These pre-clinical in vitro studies suggest that benefit may accrue from combining SP with either 5-FU or cisplatin and provide a basis for their clinical evaluation in colo-rectal tumours or transitional cell cancer of the bladder, respectively.

Antineoplastic Agents↗
PubMed1985

A phase II study of spirogermanium in patients with metastatic malignant melanoma. An NCI Canada Clinical Trials Group Study.

The National Cancer Institute of Canada Clinical Trials Group conducted a phase II study of spirogermanium given daily for 5 days every 3 weeks to previously untreated patients with malignant melanoma. In 21 evaluable patients one complete response was seen (response rate 5%). Disease progression occurred in the other 20 patients. Toxicity was primarily neurologic and mild or moderate in most patients, though there was one treatment related death. In this schedule spirogermanium has extremely limited activity against malignant melanoma and will not contribute significantly to the systemic therapy of this disease.

Adult↗
PubMed1991

Phase I evaluation of spirogermanium and 5-fluorouracil in colorectal carcinoma.

We have conducted a phase I study to evaluate the toxicity and tolerance of a 5 day continuous infusion of spirogermanium and 5-fluorouracil, (5-FU). The 5-FU was administered via a peripheral vein at 1000 mg/M2/day for 5 days by continuous infusion. Simultaneously, spirogermanium was administered via an indwelling central venous catheter by continuous infusion for 5 days starting at 50 mg/M2/day and escalating to 250 mg/M2/day. Sixteen patients received a total of 54.5 courses of therapy. The most common and severe toxicity was neurotoxicity. Mild to moderate gastrointestinal toxicity also occurred. No significant hematologic toxicity occurred. Two partial responses occurred lasting 11 and 20.5 months, both at the 100 mg/M2/day level of spirogermanium. The recommended phase II dosages are 5-FU 1000 mg/M2/day and spirogermanium 200 mg/M2/day by 5 day continuous infusion with escalation of the spirogermanium in selected individuals. Patients on long term therapy should have close neurologic evaluation and follow up. Consideration should also be given to evaluating a group of patients at the 100 mg/M2/day level of spirogermanium due to the responses seen at this level.

Adenocarcinoma↗