Ether-linked Derivatives Research Articles

Synthesis and Anticancer and Antimicrobial Evaluation of Novel Ether-linked Derivatives of Ornidazole.

Some novel 1-(2-methyl-5-nitro-1H-imidazol-1-yl)-3-(substituted phenoxy)propan-2-ol derivatives (3a-g) were designed and synthesized. Compounds 3a-g were obtained by refluxing ornidazole (1) with the corresponding phenolic compounds (2a-g) in the presence of anhydrous K2CO3 in acetonitrile. Following the structure elucidation, the in vitro antimicrobial activity and cytotoxic effects of compounds 3a-g on K562 leukemia and NIH/3T3 mouse embryonic fibroblast cells were measured. As a part of this study, the compliance of the compounds with the drug-likeness properties was evaluated. The physico-chemical parameters (log P, TPSA, nrotb, number of hydrogen bond donors and acceptors, logS) were calculated using the software OSIRIS. All the synthesized compounds except 3a showed significant activity (MIC=4-16 μg mL-1) against the bacterial strain Bacillus subtilis as compared to the standard drug, whereas antileukemic activities were rather limited. Furthermore, all the compounds were nontoxic and the selectivity index outcome indicated that the antileukemic and antimicrobial effects of the compounds were selective with good estimated oral bioavailability and drug-likeness scores.

Synthesis of new derivatives of 2,2-dimethyl-2,3-dihydro-7-benzo[b]furanol with potential antimicrobial activity

A series of 13 new ether-linked derivatives of 2,2-dimethyl-2,3-dihydro-7-benzo[b]furanol have been designed and synthesized. Ten of them were evaluated for their potential antimicrobial activity against some Gram-positive and Gram-Negative bacteria and fungi of the Candida species.

Preclinical Pharmacology of a Nonsteroidal Ligand for Androgen Receptor-Mediated Imaging of Prostate Cancer

Proper management of prostate cancer patients is highly dependent on the spread of the disease. High expression levels of the androgen receptor (AR) in prostate tumor offer a target for identifying cancer metastasis. We investigated the use of nonsteroidal AR ligands for receptor-mediated imaging as a diagnostic tool for prostate cancer staging. Compound S-26 [S-3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-(4-cyano-3-iodophenyl)-propionamide]was identified from a series of iodinated ether-linked derivatives of bicalutamide due to its high-AR binding affinity of 3.3 nM (which is similar to testosterone and approximately 25% of the binding affinity of dihydrotestosterone) in an in vitro competitive binding assay using rat prostate cytosol. Furthermore, S-26 exhibited a greater binding affinity (K(i) = 4.4 nM) in a whole-cell binding assay using COS-7 cells transfected with human AR than testosterone (K(i) = 32.9 nM) and dihydrotestosterone (K(i) = 45.4 nM). We also confirmed that sex hormone-binding globulin (SHBG), a plasma protein that binds steroids with high affinity, does not bind with S-26. Cotransfection studies with the estrogen, progesterone, and glucocorticoid receptor indicated that S-26 does not cross-react with other members of the steroid hormone receptor family. The nonsteroidal structure, high-AR binding affinity, specificity, and lack of binding to SHBG indicate that S-26 exhibits favorable properties for further development as an imaging agent for prostate cancer.

Hydrolytic Stabilization of Protected p-Hydroxybenzyl Halides Designed as Latent Quinone Methide Precursors

The hydrolysis rates of a series of protected p-hydroxybenzyl halides designed to generate a p-quinone methide through 1,6-elimination following photolytic deprotection have been investigated in order to optimize hydrolytic stability. A number of p-hydroxybenzyl halides containing an ether- or carbonate-linked photolabile hydroxy protecting group and a fluoride, chloride, or bromide benzylic leaving group have been synthesized. The hydrolysis rates of these derivatives in different water/acetonitrile mixtures and temperatures have been determined. The hydrolysis half-life of the benzyl bromide with the p-hydroxy protected as the carbonate-linked α-methylnitroveratryl (18c) is more than 750 times that of the ether-linked analogue (16c). These studies afford a Hammett σp+ of +0.28 for the carbonate-linked derivatives compared to a σp+ of −0.39 for the ether-linked derivatives. The theoretical hydrolysis half-life of the most stable benzyl fluoride in 100% water was sufficiently long so as to preclude extrapolation, while the chloride was approximately 50 h, and even the bromide was estimated to be nearly 5 h.

Synthesis of deoxy analogues of (2→8)-linked 3-deoxy-α-D-manno-oct-2-ulopyranosylonic acid (Kdo) disaccharides for binding studies with Chlamydia specific monoclonal antibodies

Deoxy analogues of the Chlamydia-specific, α-(2→8)-linked Kdo disaccharide epitope modified at the pyranose ring of the terminal Kdo unit have been prepared. Utilizing the 3,5-dideoxy-D-arabino-oct-2-ulosonate bromide donor [1] and the acceptor [2] under Helferich conditions, the 5-deoxy-α-Kdo-(2→8)-α-Kdo disaccharide [3] was obtained as the minor product together with unsaturated, α-(2→8)-glycosidically and (4→8)-ether-linked derivatives [5] and [7] as the major components. Deprotection afforded the disaccharide allyl glycosides [4], [6], and [8]. Further transformation of protected intermediates by hydrogenation followed by deblocking gave the propyl glycosides [12], [14] and [17]. The compounds may be used for binding studies with Chlamydia-specific and cross-reactive, Kdospecific monoclonal antibodies.

Synthesis and biological evaluation of ether-linked derivatives of phosphatidylinositol.

The synthesis of two novel glycero-3-phosphoinositol ether lipid analogues, rac-1-O-octadecyl-2-O-methylglycero-3-phospho-myo-inositol 6 (an ether lipid analogue of rac-1-O-octadecyl-2-O-methylglycero-3-phosphocholine; ET-18-OMe) and rac-1-O-octadecyl-2-O-acetylglycero-3-phospho-myo-inositol 11 (an ether lipid analogue of platelet-activating factor), is described. The two target compounds and the synthetic intermediates were evaluated for inhibition of HL60, BG1, and BG3 human malignant cells in vitro and inhibition of protein kinase C. Tumor inhibitory activity was found for compounds 6 and 11 in all systems but not for their synthetic intermediates. However, compounds 6 and 11 as well as the synthetic intermediates 5 and 13, but not 9, exhibited protein kinase C inhibitory activity.