Synthesis and in vitro biological activity of retinyl polyhydroxybenzoates,novel hybrid retinoid derivatives

A new hybrid derived from retinol was designed to improve the stability and anti-oxidant activity of retinol and also to add whitening properties besides its usual anti-aging properties. A variety of polyhydroxybenzoates of retinol were prepared either by base-catalysis or by direct esterification of retinol and screened for such desirable properties by analyzing the in vitro biological activity of the hybrids. Some of the retinol derivatives enhanced their thermal stability and decreased photosensitivity, and exhibited an activity in collagen synthesis similar to that of retinol. In addition, the retinyl gallate 6 showed higher activities in free radical scavenging and melanogenesis inhibition than retinol. Thus, owing to its excellent stabilities, retinyl gallate 6 may be conveniently used not only as an additive for cosmetics for prevention and improvement of skin aging and whitening but also as medicine for the treatment of skin troubles.     

Synthesis and in vitro sodium channel blocking activity evaluation of novel homochiral mexiletine analogs

New chiral mexiletine analogs were synthesized in their optically active forms and evaluated in vitro as use‐dependent blockers of skeletal muscle sodium channels. Tests carried out on sodium currents of single muscle fibers of Rana esculenta demonstrated that all of them exerted a higher use‐dependent block than mexiletine. The most potent analog, (S)‐3‐(2,6‐dimethylphenoxy)‐1‐phenylpropan‐1‐amine (S)‐( 5 ), was six‐fold more potent than (R)‐Mex in producing a tonic block. As observed with mexiletine, the newly synthesized compounds exhibit modest enantioselective behavior, that is more evident in 3‐(2,6‐dimethylphenoxy)butan‐1‐amine ( 3 ). Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Synthesis and biological evaluation on novel analogs of 9-methylstreptimidone,an inhibitor of NF-κB

Synthesis of 9-methylstreptimidone analogs and their inhibitory activities against NF-κB (nuclear factor-κB) are reported. Among several active derivatives synthesized in this study, 8 with a relatively simple structure, exhibited inhibitory activity against LPS-induced NO production comparable to that of 9-methylstreptimidone.     

Synthesis, biological activity and conformational analysis of cyclic GRF analogs

A novel cyclic GRF analog, cyclo(Asp8-Lys12)-[Asp8,Ala15]-GRF(1-29)-NH2, i.e. cyclo8,12[Asp8,Ala15]-GRF(1-29)-NH2, was synthesized by the solid phase procedure and found to retain significant biological activity. Solid phase cyclization of Asp8 to Lys12 proceeded rapidly (approximately 2 h) using the BOP reagent. Substitution of Ala2 with D-Ala2 and/or NH2-terminal replacement (desNH2-Tyr1 or N-MeTyr1) in the cyclo8,12[Asp8,Ala15]-GRF(1-29)-NH2 system resulted in highly potent analogs that were also active in vivo. Conformational analysis (circular dichroism and molecular dynamics calculations based on NOE-derived distance constraints) demonstrated that cyclo8,12[Asp8,Ala15]-GRF(1-29)-NH2 contains a long alpha-helical segment even in aqueous solution. A series of cyclo8,12 stereoisomers containing D-Asp8 and/or D-Lys12 were prepared and also found to be highly potent and to retain significant alpha-helical conformation. The high biological activity of cyclo8,12[N-MeTyr1,D-Ala2,Asp8,Ala15]-GRF(1-29)- NH2 may be explained on the basis of retention of a preferred bioactive conformation.     

Synthesis,in vitro biological activity and docking of new analogs of BIM-23052 containing unnatural amino acids

Amino Acids - Somatostatin (SST) is an endogenous cyclic tetradecapeptide hormone that exerts multiple biological activities via a family of five receptors. BIM-23052 (DC-23-99)...     

Synthesis and in vitro biological activity of retinyl retinoate, a novel hybrid retinoid derivative

A new hybrid, retinyl retinoate 1, was synthesized with a condensing reaction between retinol and retinoic acid to improve the photo-stability, and the in vitro biological activity of the hybrid was analyzed. This retinol derivative had enhanced thermal stability and decreased photosensitivity, and exhibited decreased cell toxicity compared to that of retinol. In addition, RAR activity analysis showed that retinyl retinoate 1 had higher inhibitory activity against c-Jun than retinol and showed superior effects on collagen synthesis compared to retinol. Thus, retinyl retinoate 1 may have the potential to be conveniently used as an additive in cosmetics for prevention and improvement of skin aging and medicines for the treatment of skin troubles due to its excellent stability under severe and accelerated conditions.     

Synthesis,in vitro and in vivo biological evaluation of novel graveolinine derivatives as potential anti-Alzheimer agents

A novel series of graveolinine derivatives were synthesized and evaluated as potential anti-Alzheimer agents. Compound 5f exhibited the best inhibitory activity for acetylcholinesterase (AChE) and had surprisingly potent inhibitory activity for butyrylcholinesterase (BuChE), with IC₅₀ values of 0.72 μM and 0.16 μM, respectively. The results from Lineweaver–Burk plot and molecular modeling study indicated non-competitive inhibition of AChE by compound 5f. In addition, these derivatives showed potent self-induced β-amyloid (Aβ) aggregation inhibition. Moreover, 5f didn’t show obvious toxicity against PC12 and HepG2 cells at 50 μM. Finally, in vivo studies confirmed that 5f significantly ameliorates the cognitive performances of scopolamine-treated ICR mice. Therefore, these graveolinine derivatives should be thoroughly and systematically studied for the treatment of Alzheimer’s disease.     

Synthesis and biological activity of glycosylated analogs of somatostatin

The synthesis by solid-phase methodology of two glycosylated analogs of somatostatin [Glc-Asn⁵]-SS and [NAcGlc-Asn⁵]-SS is described. These two analogs have been biologically tested on the secretion of pituitary growth hormone, pancreatic glucagon and insulin. The results show that glycosylation of somatostatin on the Asn⁵ residue decreases by a hundred fold the inhibition activity on GH release when tested $\text{in}$$\text{vitro}$. $\text{In}$$\text{vivo}$, since the activity is similar to somatostatin the carbohydrates are probably removed by some enzymatic reaction and thus liberate the full activity of somatostatin.     

Synthesis and biological activity of cyclic analogs of angiotensin

Biological properties of five novel angiotensin analogues synthesized, using the conventional methods of peptide chemistry, have been studied. Cyclization was attained by means of amide linkage with the aid of diphenylphosphorylazide or pentafluorophenyl esters. Unlike the natural hormone, the cyclic analogues of angiotensin show no pressor activity, but elicit a depressor effect untypical of angiotensin. A slight pressor activity was exhibited by the compound containing aspartic acid in position 1. The cyclic analogues in question release histamine from peritoneal mast cells in rats.     

Synthesis and biological evaluation of non-polyene analogs of amphotericin B

Synthesis of the first analog of a polyene macrolide antibiotic containing a rigid, non-polyene backbone has been accomplished. The sterol recognition surface of amphotericin B has been modified in an effort to better understand the role of the polyene backbone. Its antifungal activity is reduced significantly compared with amphotericin B.     

Synthesis,biological evaluation and structural analysis of novel peripherally active morphiceptin analogs

Morphiceptin (Tyr-Pro-Phe-Pro-NH₂), a tetrapeptide amide, is a selective ligand of the μ-opioid receptor (MOR). This study reports the synthesis and biological evaluation of a series of novel morphiceptin analogs modified in positions 2 or/and 4 by introduction of 4,4-difluoroproline (F₂Pro) in l or d configuration. Depending on the fluorinated amino acid configuration and its position in the sequence, new analogs behaved as selective full MOR agonists showing high, moderate, or relatively low potency. The most potent analog, Tyr-F₂Pro-Phe-d-F₂Pro-NH₂, was also able to activate the κ-opioid receptor (KOR), although with low potency. Docking studies and the comparison of results with the high resolution crystallographic structure of a MOR-agonist complex revealed possible structure–activity relationships of this compound family.     

Synthesis,in vitro and in vivo antitumor and antiviral activity of novel 1-substituted benzimidazole derivatives

Abstract

A novel series of 5-nitro-1H-benzimidazole derivatives substituted at position 1 by heterocyclic rings was synthesized. Cytotoxicity and antiviral activity of the new compounds were tested. Compound 3 was more active than doxorubicin against A-549, HCT-116 and MCF-7. However, compound 3 showed no activity against human liver carcinoma Hep G-2 cell line. Compounds 9 and 17b (E) showed potency near to doxorubicin against the four cell lines. The acute toxicity of compound 9 on liver cancer induced in rats was determined in vivo. Interestingly, it showed restoration activity of liver function and pathology towards normal as compared to the cancer-bearing rats induced by DENA. Compounds 17a (Z), 17b (E) and 18a (Z) were the most promising compounds for their antiviral activity against rotavirus Wa strain.     

Synthesis,in vitro biological activity,hydrolytic stability and docking of new analogs of BIM-23052 containing halogenated amino acids

One of the potent somatostatin analogs, BIM-23052 (DC-23-99) d-Phe-Phe-Phe-d-Trp-Lys-Thr-Phe-Thr-NH₂, has established in vitro growth hormone inhibitory activity in nM concentrations. It is also characterized by high affinity to some somatostatin receptors which are largely distributed in the cell membranes of many tumor cells. Herein, we report the synthesis of a series of analogs of BIM-23052 containing halogenated Phe residues using standard solid-phase peptide method Fmoc/OtBu-strategy. The cytotoxic effects of the compounds were tested in vitro against two human tumor cell lines—breast cancer cell line and hepatocellular cancer cell line, as well as on human non-tumorigenic epithelial cell line. Analogs containing fluoro-phenylalanines are cytotoxic in μM range, as the analog containing Phe (2-F) showed better selectivity against human hepatocellular cancer cell line. The presented study also reveals that accumulation of halogenated Phe residues does not increase the cytotoxicity according to tested cell lines. The calculated selective index reveals different mechanisms of antitumor activity of the parent compound BIM-23052 and target halogenated analogs for examined breast tumor cell lines. All peptides tested have high antitumor activity against the HepG2 cell line (IC₅₀ ≈ 100 μM and SI > 5) compared to breast cells. This is probably due to the high permeability of the cell membrane and the higher metabolic activity of hepatocytes. In silico docking studies confirmed that all obtained analogs bind well with the somatostatin receptors with preference to ssrt3 and ssrt5. All target compounds showed high hydrolytic stability at acid and neutral pH, which mimic physiological condition in stomach and human plasma.

     

Synthesis and biological activity of N-methylated analogs of endomorphin-2

In this paper, we describe the synthesis of a series of endomorphin-2 analogs containing N-methylated amino acids, consecutively in each position. The μ-opioid receptor binding affinities of the new analogs were determined in the displacement experiments. Their in vivo antinociceptive activity was assessed in the hot-plate test in mice after central (icv) and peripheral (ip) administration. [Sar²]endomorphin-2, which had the highest μ-receptor affinity, also showed the strongest analgesic effect when administered centrally and was the only analog that retained activity after peripheral injection.     

Synthesis and antibacterial activity of novel water-soluble nocathiacin analogs

Semi-synthetic water-soluble analogs were synthesized from nocathiacin I through the formation of a versatile intermediate nocathiacin amine 5, and subsequent transformation via reductive amination, acylation or urea formation. Several of the novel analogs displayed much improved aqueous solubility over 1, while retained antibacterial activity. Compound 15 and 16 from the amide series, demonstrated excellent in vitro and in vivo antibacterial activity.     

Synthesis and antimitotic activity of novel 2-methoxyestradiol analogs

The syntheses and antimitotic activity of several novel 2-methoxyestradiol analogs are described. Structural modifications investigated include introduction of additional unsaturation in rings B and D; inversion at C-13; and substitution at the C-2, C-15, C-16, and C-7 alpha positions. Of 15 analogs synthesized, 2 have demonstrated superior biological activities compared to 2-methoxyestradiol.     

Synthesis and biological activity of novel oxazolidinones

A number of 5-substituted derivatives of Ranbezolid, a novel oxazolidinone were synthesized. Antibacterial activity of the compounds against a number of sensitive and resistant bacteria showed promising results.     

Synthesis, biological activity and conformation of enkephalin analogs structurally related to kyotorphin

[D-Arg2,Leu5]Enkephalin and two series of its N-terminal short-chain analogues with a free and modified C-terminal carboxylic group, viz. amides and ethyl esters of tri- and tetrapeptides, were synthesized in solution and by solid-phase method. Their analgesic activity, assayed by the "tail pinch" method following intracisternal and intravenous administration to mice, was compared with activity of enkephalins and morphine. To study the space structure of the synthesized compounds, conformational calculations and fluorescence spectroscopy were applied to measure distance between aromatic nuclei of tyrosine and phenylalanine residues in the two tetrapeptides. Ethyl esters of the tri- and tetrapeptides exceed in analgesic activity the corresponding carboxylic acids and amides. In contrast to the pentapeptide, the tetrapeptide analogues were active upon intravenous administration. Conformational aspects of this series of analogues are discussed in detail; the abrupt increase in activity upon transition from tri- to tetrapeptides does not appear to be related to conformational changes.     

Nocathiacin I analogues: synthesis, in vitro and in vivo biological activity of novel semi-synthetic thiazolyl peptide antibiotics

Several nocathiacin I analogues (4-35) were synthesized and evaluated for their antibacterial activity. Most of these semi-synthetic analogues retained very good in vitro and in vivo antibacterial activity of 1.