PubMed Health⌕ Search

Biomedical subjects

H Maehr

Publications and source records attributed to H Maehr.

At least 19 recordsLinked to original sources
PubMed2005

Colon cancer and solar ultraviolet B radiation and prevention and treatment of colon cancer in mice with vitamin D and its Gemini analogs.

It has been recognized that people who live at higher latitudes and who are vitamin D deficient are at higher risk of dying from many common cancers including colon cancer. To evaluate the role of vitamin D deficiency on colon tumor growth, Balb/c adult male mice were fed either a vitamin D sufficient or vitamin D deficient diet for 10 weeks. Mice were arranged into groups of six and each animal received subcutaneously 10(4) MC-26 cells in the posterior trunk. The tumor size was recorded daily. By day 9 there was a significant difference in tumor volume between the vitamin D sufficient and vitamin D deficient mice. By day 18 the vitamin D deficient animals had a tumor size that was 56% larger compared to the animals that were vitamin D sufficient. To determine whether treatment with active vitamin D analogs could further decrease colon tumor growth in a vitamin D sufficient state, groups of mice were treated with the novel 19-nor-Gemini compounds. The mice were fed a low calcium diet. Twenty-four hours after tumor implantation, the mice received, three times weekly, one of the vitamin D analogs or the vehicle. The group that received Gemini 1,25-dihydroxy-21(3-hydroxy-3-trifluoromethyl-4-trifluoro-butynyl)-19-nor-20S-cholecalciferol (3) showed a dose-dependent decrease in tumor volume. On day 19, at the dose level of 0.02microg molar equivalents (E), the tumor volume was reduced by 41% when compared to the control group. At the same time point, the hexadeuterated analog 1,25-dihydroxy-21(3-hydroxy-3-trifluoromethyl-4-trifluoro-butynyl)-26,27-hexadeutero-19-nor-20S-cholecalciferol (4), administered at the 10-fold lower dose of 0.002microgE, showed a 52% reduction in tumor volume (p<0.05), compared to the control group. Animals that received 1,25(OH)(2)D(3) at 0.002 and 0.02microg showed a trend in tumor volume reduction at the highest dose but the changes were not statistically significant. An evaluation of serum calcium concentrations revealed that the calcium levels were normal in all groups, except the group receiving 0.02microgE of 4. The results from these studies demonstrate that vitamin D deficiency may accelerate colon cancer growth and that novel Gemini analogs of 1,25(OH)(2)D(3) may be an effective new approach for colon cancer treatment.

Animals↗
PubMed1997

Structure optimization of a leukotriene D4 antagonist by combinatorial chemistry in solution.

Structure optimization of the leukotriene D4 antagonist Ro24-5913 was attempted by combinatorial chemistry. Three segments in its N-succinyl-3-(2-thiazolylethenyl)anilide skeleton, designated as A, B, and C coincided with the thiazolyl, aniline, and N-acyl moieties, respectively, and were selected for variations in a synthesis involving the sequences A + B-->AB and AB + C-->ABC to furnish the library (10A 7B 10C) containing 700 compounds. Lead candidates were identified by the LTD4-induced muscle-contraction assay. Assays of the C-partition 10(10A 7B C) of the set led to a subset of C elements associated with significant bioactivities, ic = {C1, C2, C3}, from which the preferred element C1 was selected. Incorporating this selection into the synthesis of the first reduced set gave the partition 7(10A B C1) whose assay revealed the set iB = {B1, B6} and hence the preferred B element B1. The second reduced set, 10(A B1 C1) incorporating the selected C1 and B1 moieties, revealed iA = {A1, A3, A4, A6, A7, A8, A9} In the resulting combinatiorial product iA x iB x iC, comprising 42 elements, A1 B1 C1 appears on top of the list. Thus, 4-[[3-[2-[4-(2,2-dimethyl ethyl)cyclobutyl-2-thiazolyl]ethenyl] phenyl]amino]-2,2-diethyl-4-oxobutanoic acid (Ro24-5913) was confirmed as the structure with the highest bioactivity. Analogues obtained by replacement of the cyclobutyl group in Ro24-5913 with 4-fluorophenyl and t-butyl were the runners-up. Of these, the former exhibited bioactivity comparable to that of Ro24-5913.

Animals↗
PubMed1995

An alternate synthesis of the Tat-antagonist 7-chloro-N-methyl-5-(1H-pyrrol-2-yl)-3H-1,4-benzodiazepin-2-amine.

An alternative synthesis of 7-chloro-N-methyl-5-(1H-pyrrol-2-yl)-3H-1,4-benzodiazepin-2-amine, the compound that inhibits gene expression by HIV-1 at the level of transcriptional transactivation by Tat, has been developed. The process is based on ring expansion of 6-chloro-2-chloromethyl-4-(1H-pyrrol-2-yl)quinazoline 3-oxide which leads to the corresponding benzodiazepine Ro24-7429. Quinazoline 3-oxide formation in the presence of boron trifluoride gives a tetracyclic system containing a 2,2-difluoro-1,3,6,2-oxadiazaborine ring that survives ring expansion to 13-chloro-5,5-difluoro-9-(methylamino)-5H-pyrrolo[1',2':3,4]- 1,3,6,2-oxadiazabora[6,5-d]-8H-1,4-benzodiazepin-7-ium hydroxide inner salt. This unusual benzodiazepine does not significantly inhibit Tat-mediated gene expression by HIV-1.

Benzodiazepines↗
PubMed1986

Microbial products. VIII. Azinothricin, a novel hexadepsipeptide antibiotic.

Azinothricin was isolated from the culture filtrate of Streptomyces sp. X-14950 in crystalline form. It represents a new type of hexadepsipeptide antibiotic as it contains a 19-membered cyclodepsipeptide ring composed of six unusual amino acids and bearing a novel C21 side chain. Azinothricin was identified as [(3S,4S,7R(S*),10S,17R,20S,23R)[2S(2'R*,5'S*, 6'S*)3S*]]-alpha-ethyl-6-(3-ethyl-1, 5-dimethyl-4-oxo-1,5-heptadienyl)- N-(1,8, 14,15,18,21,27-heptaaza-21-hydroxy-7-(1-hydroxyethyl)-2,6,9,16,19, 22-hexaoxo-4-isopropyl-20-(methoxy-methyl)-17,18-dimethyl-5-oxa tricyclo [21.4.0.0(10,15)]heptacosan-3-yl)tetrahydro-alpha, 2-dihydroxy-5-methyl-2H-pyran-2-acetamide and is primarily active against Gram-positive microorganisms.

Anti-Bacterial Agents↗
PubMed1982

Microbial products. VI Five novel metabolites related to benz[a]anthracene from an unidentified actinomycete designated X-14881.

Five metabolites of actinomycete X-14881 were isolated from the fermentation broth and characterized. The major component was identified as [3R-(3 alpha,6a beta,7 beta,12 alpha,12a alpha)] or [3S-(3 beta,6a alpha, 7 alpha,12 beta,12a beta)]-6a, 7,12-trihydroxy-3,4,6a, 7,12, 12a-hexahydro-8-methoxy-3-methylbenz[a]-anthracen-1(2H)-one; the other four are closely related derivatives thereof.

Actinomycetales↗
PubMed1980

Microbial products. IV. X-14847, a new aminoglycoside from Micromonospora echinospora.

Micromonospora echinospora strain X-14847 produces gentamicin A as the major antibiotic together with a new aminoglycoside, termed X-14847, and identified as a 2-amino-2-deoxy-alpha-D-glucopyranosyl myo-inositol. This report describes the taxonomy of the culture, fermentation conditions, the isolation and the identification of X-14847.

Aminoglycosides↗
PubMed1979

Antibiotic X-5108. IX. Chemical conversion of mocimycin to aurodox and derivatives of aurodox, goldinamine and mocimycin.

Mocimycin was converted to the acylesters by selective acylation of the hydroxyl group of the 4-hydroxy-1-methyl-2(1H)pyridinone moiety. Subsequent N-methylation at the nuclear nitrogen and removal of the protective group from the resulting reaction products afforded aurodox. Mono-O-acetylmocimycin and several analogous aurodox esters thus prepared possess antibacterial activity in vitro and growth-promotion properties in poultry. Esters of aurodox involving the hydroxyl group of the 4-hydroxy-1-methyl-2(1H)pyridinone moiety are activated. Accordingly, acetic acid treatment of the aurodox esters generates O-acylgoldinamines which undergo transacylation furnishing N-acylgoldinamines. Alternatively, N-acylgoldinamines can be prepared by selective mono--o-arylsulfonylation of aurodox, liberating o-arylsulfonylgoldinamine by treatment with acetic acid followed by N-acylation and removal of the protective arylsulfonyl group. A third approach to N-acylgoldinamines consists in direct N-acylation of goldinamine itself which is prepared by acetic acid treatment of aurodox. None of these derivatives prepared, however, exhibited significant antimicrobial or growth-promoting properties, suggesting that goldinonic acid moiety, or a closely related derivative thereof, is required for biological activity.

Acylation↗
PubMed1978

Antimetabolites produced by microorganisms XVI. Synthesis of N5-hydroxy-2-methylarginine and N5-hydroxy-2-methylornithine.

N5-Hydroxy-2-methylornithine and N5-hydroxy-2-methylarginine were synthesized. 2-Amino-5-hydroxy-2-methylpentanoic acid was prepared from 5-hydroxy-2-pentanone and converted to N-(tetrahydro-3-methyl-2-oxo-2H-pyran-3-yl) acetamide which was treated with hydrogen bromide affording 2-(acetylamino)-5-bromo-2-methylpentanoic acid. This acid was esterified with methanol and used to alkylate anti-benzaldoxime yielding methyl 2-(acetylamino)-2-methyl-5-[(phenylmethylene)amino]-pentanoate N5-oxide which, upon hydrolysis, yielded N5-hydroxy-2-methylornithine, and, upon aminolysis and short acid-treatment, gave N2-acetyl-N5-hydroxy-2-methylornithinamide. Carbamimidoylation and hydrolysis of the latter compound furnished N5-hydroxy-2-methylarginine.

Antimetabolites↗
PubMed1977

Separation of gentamicin C-complex into five components by Craig distribution.

A gentamicin C-complex preparation was separated preparatively into five components by Craig distribution. Gentamicins C1, C2, and C1a were the major components, whereas components C2a and C2b represented only 4% of the total C-complex mixture. Paper chromatographic analysis showed that the gentamicin C2b separated by Craig distribution was identical with a gentamicin isolated from Micromonospora purpurea var. JI-33 fermentation broth and identified as 6'-N-methylgentamicin C1a. Similarly, component C2a was identical with a previously separated gentamicin component tentatively identified as the 6'-C epimer of gentamicin C2.

Biological Assay↗
PubMed1976

Antimetabolites produced by microorganisms. XV Synthesis of 2-methyl-L-arginine, 2-methyl-L-ornithine and their enantiomers.

5-(3-Azidopropyl)-5-methyl-2, 4-imidazolidinedione was prepared either from 5-(3-chloropropyl)-5-methyl-2,4-imidazolidinedione or 5-methyl-5-(3-[(4-methylphenyl)sulfonyloxy]-propyl)-5-methyl-2, 4-imidazolidinedione and hydrogenolyzed to the corresponding amine which, after carbamimidoylation, afforded 2-methyl-DL-arginine upon acid hydrolysis. Racemic 2-methylarginine was converted enzymically to a mixture of 2-methyl-D-arginine and 2-methyl-L-ornithine. 2-Methyl-L-arginine was reconstructed from 2-methyl-L-ornithine via its Cu(II) chelate with O-methyl-isourea and 2-methyl-D-ornithine was obtained by alkaline hydrolysis of 2-methyl-D-arginine.

Arginine↗