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At least 181 records · Page 10Linked to original sources
PubMed2000

Formal total synthesis of (+)-diepoxin sigma.

The highly oxygenated antifungal anticancer natural product (+/-)-diepoxin sigma was prepared in 10 steps and in 15% overall yield from O-methylnaphthazarin. Highlights of the synthetic work include an Ullmann coupling and a possibly biomimetic oxidative spirocyclization for the introduction of the naphthalene ketal as well as the use of a retro-Diels-Alder reaction to unmask the reactive enone moiety in the naphthoquinone bisepoxide ring system. A novel highly bulky chiral binaphthol ligand was developed for a boron-mediated Diels-Alder reaction that constitutes a formal asymmetric total synthesis of (+)-diepoxin sigma.

Africa↗
PubMed2005

Aromatic derivatives and tellurium analogues of cyclic seleninate esters and spirodioxyselenuranes that act as glutathione peroxidase mimetics.

[Reaction: see text]. Several novel organoselenium and tellurium compounds were prepared and evaluated as mimetics of the selenoenzyme glutathione peroxidase, which protects cells from oxidative stress by reducing harmful peroxides with the thiol glutathione. The compounds were tested for catalytic activity in a model system wherein tert-butyl hydroperoxide or hydrogen peroxide were reduced with benzyl thiol and the rate of the reaction was measured by monitoring the formation of dibenzyl disulfide. Thus, aromatic derivatives 19, 22, 24, and 25 proved to be inferior catalysts compared to the parent cyclic seleninate ester 14 and spirodioxyselenurane 16. In the case of 19 and 22, this was the result of their rapid conversion to the relatively inert selenenyl sulfides 31 and 32, respectively. In general, hydrogen peroxide was reduced faster than tert-butyl hydroperoxide in the presence of the selenium-based catalysts. The cyclic tellurinate ester 27 and spirodioxytellurane 29 proved to be superior catalysts to their selenium analogues 14 and 16, respectively, resulting in the fastest reaction rates by far of all of the compounds we have investigated to date. Oxidation of 29 with hydrogen peroxide produced the unusual and unexpected peroxide 33, in which two hypervalent octahedral tellurium moieties are joined by ether and peroxide bridges. The structure of 33 was confirmed by X-ray crystallography. Although 33 displayed strong catalytic activity when tested independently in the model system, its relatively slow formation from the oxidation of 29 rules out its intermediacy in the catalytic cycle of 29.

Benzyl Compounds↗
PubMed2001

First total synthesis of (+/-)-stemonamide and (+/-)-isostemonamide.

[structure: see text] The total synthesis of the tetracyclic alkaloids stemonamide (1) and isostemonamide (2) is presented. The key step is the reaction between a silyloxyfuran and an N-acyliminium ion. The second quaternary center is created by an intramolecular aldol spirocyclization. After 1,4-addition of an appropriate side chain, the methyl and double bond are installed by Mannich reaction. The seven-membered ring is closed by intramolecular nucleophilic displacement.

Alkaloids↗
PubMed2002

Stereocontrolled [3 + 2] annulations with arene chromium tricarbonyl complexes: construction of spirocyclic compounds related to fredericamycin A.

[reaction: see text] An efficient method has been developed for the stereocontrolled construction of polycyclic and spirocyclic compounds, including the spirocyclic core of the antitumor agent fredericamycin A. The strategy involves a one-pot aldol addition/Brook rearrangement/cyclization sequence beginning from arene chromium tricarbonyl complexes and can formally be described as a [3 + 2] annulation.

Antibiotics, Antineoplastic↗
PubMed2004

Syntheses of the C(1-6) and C(19-24) fragments of lituarines A, B, and C.

[structure: see text] Lituarines A-C are marine natural products comprising a tricyclic spiroacetal bridged at C(8) and C(18) by a functionalized ester linkage conceptually obtained from a C(19-24) alcohol and a C(1-6) carboxylic acid whose oxidation level varies at C(4) and C(5). Stereoselective routes are described to compounds 26 and 27, fully functionalized ester fragments of lituarine A and lituarines B and C, respectively.

Epoxy Compounds↗
PubMed2005

Progress in the synthesis of the lituarines: stereocontrol in sequential C-C bond formation on a spirobutenolide template.

[structure: see text] We describe elaboration of a tricyclic spirobutenolide corresponding to the C(7-18) tricyclic substructure common to lituarines A-C. Conjugate addition, to install the C(16) methyl, is followed by construction of the crucial C(18-19) bond by silyl enol ether addition to the derived spiroacetal C(18)-O oxonium ion. Esterification with a C(1-6) acid, and selective ozonolysis to release the C(23) carbonyl, complete the assembly of all the carbons present in the lituarine macrocyclic core.

4-Butyrolactone↗
PubMed2006

Chemical variation of natural product-like scaffolds: design and synthesis of spiroketal derivatives.

The design and synthesis of spiroketal structures and their chemical modification, leading to a collection of new small molecules for biological evaluation as orally-bioavailable lead compounds is described. Both [6,5]- and [6,6]-membered ring spiroketal units have been prepared in a stereochemically-varying fashion starting from commercially available (R)- or (S)-glycidol, in ten, eleven and twelve linear steps, in overall yields of 45, 40 and 20%, respectively. Further elaboration according to Lipinski's guidelines has given a collection of structurally-diverse, new spiroketal derivatives in high yields and with high purity.

Biological Availability↗
PubMed1988

In vitro assessment of antimicrobial agents against Toxoplasma gondii.

We have modified a method of quantitating growth of Toxoplasma organisms by measuring incorporation of [3H]uracil into Toxoplasma-infected, differentiated L6E9 rat myocytes and have found that low-dose pyrimethamine (0.1 microgram/ml) and sulfadiazine (25 micrograms/ml) are synergistic. Pyrimethamine at higher concentrations (0.5 and 1.0 micrograms/ml) inhibits uptake to the same degree as the low-dose pyrimethamine-sulfadiazine combination. Spiramycin was effective only at high concentrations (200 micrograms/ml) and with prolonged incubation of greater than 72 h. Clindamycin and several of its analogues, methotrexate and difluoromethylornithine, were all ineffective and showed no additive effect with either pyrimethamine or sulfadiazine. Spirogermanium, an experimental antineoplastic and antiprotozoan agent, was effective only at concentrations close to those toxic to the system. 5-Fluorouracil was effective even at 0.1 microgram/ml. At 0.01 microgram/ml it was synergistic with pyrimethamine (0.1 microgram/ml), and the combination was as effective as high-dose pyrimethamine (1.0 microgram/ml).

Animals↗
PubMed1988

A phase II study of spirogermanium in advanced large bowel cancer. An Eastern Cooperative Oncology Group study.

Thirty-one patients with advanced colorectal cancer were entered on a phase II study of spirogermanium. Of these, 23 received the drug at the dose of 200 mg/m2 intravenously (i.v.) over 4 h twice a week every week. There were 2 (9%) partial responses. No complete responses were noted. Two life-threatening and six severe toxicities were observed. We conclude that this drug has some activity against colorectal cancer.

Aged↗
PubMed1989

Phase II trial of spirogermanium and vindesine in malignant glioma.

Fifty-four adults with recurrent malignant glioma were treated on an Eastern Cooperative Oncology Group (ECOG) trial. All had previous radiation therapy, and 70% had previous chemotherapy. They were assigned to either vindesine 3 mg/m2 weekly or spirogermanium 80 mg/m2 three times weekly with escalation to 120 mg/m2. The response was 4% to vindesine, and 8% to spirogermanium. The duration of response was 53 days for a patient who had clinical improvement only, but greater than 151 days and greater than 1066 days for two patients who had achieved a greater than 50% reduction in tumor size by computed tomography (CT). The toxicities were hematologic for vindesine and neurologic for spirogermanium. Neither agent seems to have sufficient efficacy to warrant further trials in previously treated glioma patients.

Adult↗
PubMed1994

An Eastern Cooperative Oncology Group phase II study of single agent DHAD, VP-16, aclacinomycin, or spirogermanium in metastatic pancreatic cancer.

There were 80 patients with measurable metastatic or unresectable pancreatic cancer randomly assigned to treatment with either DHAD, VP-16, aclacinomycin, or spirogermanium. There were no complete or partial responses. Two deaths from leukopenia occurred in patients treated with DHAD. One patient receiving spirogermanium experienced a seizure. No other life-threatening toxicities occurred. Maximal toxicities were not significantly more frequent with any treatment group. Median survival was 10 weeks, and median time to progression was only 6 weeks, with no difference among these four therapies.

Aclarubicin↗
PubMed1983

The effects of chemotherapy on bony metastases as measured by quantitative skeletal imaging.

The effect of chemotherapy on bony metastases from adenocarcinoma of the colon was investigated by quantitative skeletal imaging over a two-month interval. The quantitative skeletal imaging results correlated with conventional blood chemistry results over this time period. While chemical assay techniques furnish an average value of lesion response, the quantitative bone scan represents a method for individual lesion analysis. This methodology has the potential to provide a better understanding of metastatic bone disease therapy.

Adenocarcinoma↗
PubMed1983

Phase I study of spirogermanium given daily.

Spirogermanium, an azaspirane compound, has recently had limited clinical trials using a schedule of intravenous injection one to three times every week. The observation of clinical antitumor activity and lack of myelosuppression prompted us to investigate further the clinical effects of spirogermanium administered on various schedules. A total of 52 patients with advanced metastatic tumors refractory to standard therapy were treated with spirogermanium. Three different schedules of drug administration were evaluated. Initially, a short daily IV infusion for 5 days every week was evaluated, starting with a dose of 30 mg/m2/day. A total of 22 patients received 69 courses with a dose range of 30-120 mg/m2/day for 5 days every week. The maximum tolerated dose was 100 mg/m2/day IV over 1 hr and 120 mg/m2 over 2-3 hr. In the second phase of the study, 12 patients received 41 courses of spirogermanium as a 24-hr continuous infusion for 5 days/wk at a dose of 150-375 mg/m2/day. The maximum tolerated dose was 200 mg/m2/day for 5 days. In the third phase of the study, 18 patients received spirogermanium as a continuous infusion daily for a median of 30 days (range 6-77 days) in a dose range of 100-200 mg/m2/day. The maximum tolerated dose was 150 mg/m2/day. Of the 44 assessable patients, 3 demonstrated a partial response and 3 had minor tumor regression; all responses occurred in lymphoma patients. The dose-limiting toxicity of spirogermanium was neurologic; other side effects consisted of mild anorexia, nausea and vomiting, and possible lung toxicity. There was no clear evidence of cumulative toxicity despite daily administration of spirogermanium. Our data suggest that spirogermanium can be administered daily by several different schedules, and the optimum dose depends on the infusion time and the duration of therapy. The delivery of drug by continuous infusion permitted administration of twofold higher dose levels compared to the standard IV schedules used in previous studies.

Adult↗
PubMedDate not supplied

Synthesis and cytotoxicity of platinum(II) complexes of 3-aminocyclopentanespiro-5-hydantoin and 3-aminocycloheptanespiro-5-hydantoin.

Four new platinum(II) complexes of 3-aminocyclopentanespiro-5-hydantoin (acpsh) and 3-aminocycloheptanespiro-5-hydantoin (achpsh) were synthesized and characterized by elemental analysis, IR and 1NMR spectra. The spectral analyses indicated a cis-square planar structure of the complexes with ligands coordinated via the NH2 group. The complexes were evaluated for in vitro cytotoxicity in murine erythroleukemia (MEL) cells, clone F4N, using cell-growth and macromolecular synthesis assay. The compounds, with exception of [Pt(NH3)(achpsh)Cl2] (IV), exhibited much lower cytotoxicity than that of cisplatin (DDP). Compound IV was nearly as cytotoxic as DDP. The new complexes exerted low antibacterial activity as assessed by seven bacterial strains.

Animals↗
PubMed1988

Effect of metal containing compounds on superoxide release from phorbol myristate acetate stimulated murine peritoneal macrophages: inhibition by auranofin and spirogermanium.

A variety of metal containing compounds were examined for their ability to inhibit the respiratory burst of murine peritoneal macrophages. Auranofin (AF), a gold containing complex used in the treatment of rheumatoid arthritis, is a potent inhibitor of the macrophage respiratory burst. Ten rhodium, iridium, osmium and ruthenium containing complexes were inactive in inhibiting superoxide production. The only active nongold organometallic complex was spirogermanium which had an equivalent IC50 for activity as AF. The inhibitory activity of AF, but not spirogermanium, was reduced in the presence of the sulfhydryl reducing agent dithiothreitol. This suggests that interactions other than those with sulfhydryl groups may be involved in the action of spirogermanium.

Animals↗