Synthesis and biological activity of some structural modifications of pancratistatin

Structurally modified derivatives of 7-deoxypancratistatin have been synthesized and evaluated in cancer cell line inhibition studies.     

Inhibition of smooth muscle contraction and platelet aggregation by peptide 204-212 of lipocortin 5: an attempt to define some structure requirements

Peptide 204-212 of lipocortin (LC) 5 inhibited porcine pancreatic phospholipase A(2) (PLA(2)) induced rat stomach strip contractions and ADP induced rabbit platelet aggregation in a concentration dependent manner (IC(30) of 10 muM and 400 muM, respectively). The first two amino acids are not necessary since the eptapeptide 206-212 was equipotent in both assays (IC(30) of 12.5 muM and 420 muM). Of the two pentapeptides 204-208 and 208-212 only the latter showed inhibitory activity in both models although the potency was much reduced (IC(30) of 170 muM and 630 muM) compared with that of the parent nonapeptide. Comparison of peptide 204-212 effects with those of its analogues on LC1 and LC2 indicate that lysine 208 and aspartic acid 211 are essential in order to maintain a fully active nonapeptide.     

Synthesis and biological activity of some new leucine-enkephalin analogues

The opioid pentapeptide leucine-enkephalinamide and eleven of its analogues have been synthesised by the solid phase technique employing mostly 9-fluoroenylmethyloxycarbonyl amino acid active esters in the presence of 1-hydroxybenzotriazole. Both the conventional chloromethylated copolystyrene-2% divinylbenzene resin as well asp-alkoxybenzyl alcohol resin were employed and it was observed that yields were uniformly better with the latter resin. The analogues were made by affecting single or multiple replacements of amino acids involving positions 1,2 and 5. Some of the analogues were found to be more potent than morphine in the guinea pig ileum assay.     

Myelopeptide MP-5 and fluorescent derivatives: Synthesis and biological activity

The Val-Val-Tyr-Pro-Asp bone marrow peptide (MP-5) and its analogue (MP-5-Lys) were synthesized. Fluorescent derivatives, Ftc-MP-5 and MP-5-Lys(Ftc), were prepared. The iological activity of MP-5 and MP-5-Lys was studied in vitro and in vivo. The MP-5 peptide caused 60–84% inhibition of growth of the following mouse cancers: lymphatic leukemia P388, melanoma B-16, and cervical carcinoma CUC-5. These peptides also restored functional activity of T-lymphocytes that was inhibited by metabolic products of the HL-60 leukemic cell line. MP-5-Lys(Ftc) was shown to preserve the functional properties of MP-5 towards T-lymphocytes, but Ftc-MP-5 was practically inactive.     

An attempt to select for spontaneous locomotor activity in Drosophila melanogaster

Seven generations of selection for high and low spontaneous locomotor activity were made in the wild-laboratory strain Oregon of Drosophila melanogaster. Great care was taken to select for activity and not for reactivity. In opposition with the non totally unambiguous results obtained by another author, absolutely no response to selection could be obtained. Thus the Oregon strain of Drosophila melanogaster does not appear to possess any additive genetic variance for spontaneous locomotor activity. Yet before taking for granted that that conclusion is applicable to all strains of Drosophila melanogaster an experimental selection should be performed again using a freshly captured wild strain.     

Antithrombotic effects of peroxynitrite: Inhibition and reversal of aggregation in human platelets

The inhibition of platelet aggregation by peroxynitrite, a reactive oxygen species derived from the interaction of nitric oxide (NO) and superoxide, was examined in platelet-rich plasma. In this report, we have used a preparation of peroxynitrite that was free of H₂0₂ and MnO₂. As such, peroxynitrite dose-dependently (50–200 μA) inhibited aggregation of human platelets stimulated by ADP (5 μM), collagen (0.5 μg), thrombin (0.5 UlmL) and U46619 (1 PM). In addition, peroxynitrite reversed platelet aggregation induced by collagen, ADP, and thrombin. Peroxynitrite, preincubated with platelet-poor plasma or albumin (7%) for 30 min, did not alter the inhibition of platelet aggregation. This suggested that the inhibitory action of peroxynitrite may be due to nitrosylation of proteins, which by themselves possess activity, rather than conversion to NO or NO donors. Furthermore, we show that peroxynitrite increased the cGMP level only at 200 μM concentrations, further suggesting that the action of peroxynitrite was not completely due to its conversion to NO or NO donors.     

Synthesis of salicyl-peptides and their effect on human platelet aggregationin vitro

Summary A series of leucine dipeptide amides containing at their N-terminal amino group the salicyl-residue [(o)-RO-C₆H₄-CO-, where R=H or CH₃CO] have been synthesized by conventional solution techniques and tested for their inhibitory activity on human platelet aggregationin vitro induced by collagen, ADP or adrenaline. The salicyl-peptide (o)-HO-C₆H₄-CO-Leu-Asp(OBzl)-NH₂ was found to exert strong inhibitory activity on platelet aggregation induced by collagen with an IC₅₀ value 4.5 mM. The corresponding dipetide H₂N-Leu-Asp(OVzl)-NH₂ was also examined and was found to be less active, indicating that the presence of the lipophilic-benzyl ester group in combination with the salicyl group enhance the inhibitory activity. All the other salicyl-peptides examined either didn't show any inhibitory or aggregatory activity or a slight inhibition at the concentration of 9–10 mm.The abbreviations used are in accordance with the rules of IUPAC-IUB Joint Commission on Biochemical Nomenclature: Eur J Biochem (1984) 138: 9–37; J Biol Chem (1989) 264: 663–673. Additional abbreviations are: ADP adenosine diphosphate - Boc tert-butyloxycarbonyl - Bzl benzyl - DIEA N,N-diisopropylethylamine - DMSO dimethyl sulfoxide - DMF N,N-dimethylformamide - EtOAc ethyl acetate - FCC flash column chromatography - IC₅₀ molar concentration of salicyl-peptide for 50% inhibition of platelet aggregation - iso-BCF isobutyl chloroformate - NMM N-methylmorpholine - PyBOP (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate - TLC thin layer chromatography - TMS tetramethylsilane     

Synthesis and biological evaluation of some 17-picolyl and 17-picolinylidene androst-5-ene derivatives

Starting from dehydroepiandrosterone (1) 17-picolyl (2), 17-picolinylidene (7), 17-picolinylidene-16-one (10 and 11), and 17-picolyl-16-one (15) derivatives of androst-5-ene were synthesized in one, two, four and five steps respectively. By the Oppenauer oxidation or dehydration of 2, 7, 10, and 11 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), the corresponding A and B ring modified derivatives 3, 5, 6, 8, 9, and 12-14 were obtained. The structure of 2 was unambiguously proved by the appropriate X-ray structural analysis. Compounds 3, 5, 9, 12-14 showed inhibitory activity against the enzyme aromatase. Antibacterial activity, toxicity to brine shrimp Artemia salina, antitumor activity against three tumor cell lines (human cervix carcinoma HeLa cells, human melanoma FemX cells, and human myelogenous leukemia K562 cells) and toxicity against peripheral blood mononuclear cells were evaluated. Three tested compounds, namely 11, 13, and 15, showed strong activity against all three cell lines, the IC(50) values being in the range of 4-10 microM.     

Interaction of antimicrobial peptides with biological and model membranes: structural and charge requirements for activity

Species right across the evolutionary scale from insects to mammals use peptides as part of their host-defense system to counter microbial infection. The primary structures of a large number of these host-defense peptides have been determined. While there is no primary structure homology, the peptides are characterized by a preponderance of cationic and hydrophobic amino acids. The secondary structures of many of the host-defense peptides have been determined by a variety of techniques. The acyclic peptides tend to adopt helical conformation, especially in media of low dielectric constant, whereas peptides with more than one disulfide bridge adopt beta-structures. Detailed investigations have indicated that a majority of these host-defense peptides exert their action by permeabilizing microbial membranes. In this review, we discuss structural and charge requirements for the interaction of endogenous antimicrobial peptides and short peptides that have been derived from them, with membranes.     

Synthesis and biological evaluation of pyridine-linked indanone derivatives: Potential agents for inflammatory bowel disease

A series of pyridine-linked indanone derivatives were designed and synthesized to discover new small molecules for the treatment of inflammatory bowel disease (IBD). Compounds 5b and 5d exhibited strongest inhibitory activity against TNF-α-induced monocyte adhesion to colon epithelial cells (an in vitro model of colitis). In TNBS (2,4,6-trinitrobenzenesulfonic acid)-induced rat colitis model, oral administration of the compounds 5b and 5d ameliorated colitis with significant recovery in altered expressions of E-cadherin, TNF-α and IL-1β expressions, indicating 5b and 5d as potential agents for therapeutics development against IBD.     

Synthesis and biological activity of some cardiotonic compounds related to gitoxigenin

The four diastereomeric 3,16-diacetates 6, 9, 10 and 11 were prepared from gitoxin 1 by the routes shown in Schemes 1 and 2 and tested for inotropic activity in the isolated guinea-pig atrial preparation. In line with earlier findings in the digitoxigenin series, derivatives with a 3 alpha-acetoxy function, viz 9 and 10, possessed high biological activity.     

A SNARE and specific COPII requirements define ER-derived vesicles for the biogenesis of autophagosomes

The endoplasmic reticulum (ER) is a major source for the generation of autophagosomes during macroautophagy. Our recent work in yeast shows that particular ER-derived vesicles are generated for the biogenesis of autophagosomes. These vesicles not only incorporate a SNARE protein that is largely ER-resident under nonstarving conditions, but also display COPII requirements for ER-exit that differ from conventional cargo-transporting vesicles. Our results suggest that specific intracellular traffic is launched at the ER for the transport of membranes to sites of autophagosome formation.     

Synthesis and biological activity of canavanine hydrazide derivatives

Summary. The canavanine derivatives L-canavanine hydrazide (CH), L-canavanine-bis-(2-chloroethyl)hydrazide (CBCH) and L-canavanine phenylhydrazide (CPH) were synthesized and evaluated for biological activity in microorganisms, plants and tumor cells using canavanine as a positive control. (1) In microbial systems, the compounds exerted activity, as assessed in 14 bacterial strains. The effect of canavanine was easily removed by equimolar concentrations of arginine or ornithine, while the effect of CBCH or CPH was abolished by 10-fold excess of arginine or 10- to 100-fold excess of ornithine. (2) In plants, the activity of CH and CBCH were relatively low, whereas the inhibitory potential of CPH was comparable or even superior to that of canavanine, resulting at 1 mM concentration in a nearly complete block of tomato cell growth, and reducing by up to 80% the length of radicles of cress, amaranth, cabbage and pumpkin. (3) In pumpkin seeds, CPH or canavanine induced the synthesis of four small heat shock proteins of hsp-17 family in the pH range of 6 to 7.5. The proteins exhibited in both cases a similar profile, but differed in the timing of their expression and/or accumulation. With canavanine, the highest hsp-17 expression was found after 48 h of drug treatment, while with CPH this maximum was shifted to 24 h. (4) CPH proved to be highly cytotoxic against Friend leukemia cells in culture, exceeding by one order of magnitude the cytotoxicity of canavanine. The effect of canavanine was completely removed in the presence of equimolar amounts of arginine, while a 20-fold excess of arginine failed to abolish the cytotoxicity of CPH. Thus, a proper hydrazide modification of canavanine may lead to a significant increase in its growth-inhibitory activity and to a change in the mode of action of the parent compound. Received October 5, 1999, Accepted January 27, 1999     

Synthesis and biological activity of abscisic acid esters

16 ABA esters including 11 new compounds were prepared by two different esterification routes. All the structures of ABA esters were confirmed by ¹H NMR, ¹³C NMR and HRMS. Their biological activity and hydrolysis stability were investigated. Fortunately, there were 15 and 9 compounds which displayed much better or nearly the same inhibition activity for rice seedling growth and Arabidopsis thaliana seed germination compared to ABA, respectively. Especially, compounds 2d and 2g showed better biological activities than ABA in the three tests. Moreover, we found that chemical hydrolysis ability of the esters in vitro had little relationship to their biological activity.     

An efficient synthesis and biological activity of substituted p-benzoquinones

An efficient synthesis of 2,5-diarylamino-3,6-dichloro-1,4-benzoquinone derivatives has been achieved by condensing mono substituted anilines with tetrachloro-p-benzoquinone in presence of fused sodium acetate as condensing agent under microwave irradiation without any solvent. All the synthesized compounds were tested for their antibacterial and antitumour activity using standard drugs.     

Synthesis and antiproliferative activity of some diaryldiazepines and diarylpyrimidines

Novel substituted 5,7-diaryl-2,3-dihydro-1,4-diazepines and 4,6-diaryl-2-aminopyrimidines were synthesized and tested for their antiproliferative activity. Title compounds were obtained by cyclocondensation of a substituted flavone with ethylenediamine and guanidine respectively. The cytotoxicity in vitro against various human leukemic cancer cell lines viz., Jurkat, HL60, MOLT3, NCEB-1, K562 was determined.     

Synthesis and biological activity of dialkylphosphocholines

A series of dialkylphosphocholines were prepared and evaluated for their biological activity. The antiprotozoal activity was determined against Acanthamoeba lugdunensis. Compound 15 exhibited excellent trophocidal activity. None of the tested dialkylphosphocholines exhibited better fungicidal activity against Candida albicans than miltefosine. The antineoplastic activity was determined against HeLa. The most cytotoxic was compound 10, which was more active against tumor cells as against normal cells.     

A tetradecapeptide somatostatin dicarba-analog: Synthesis,structural impact and biological activity

We described here the first tetradecapeptide somatostatin-analogue where the disulfide bridge has been replaced by a carbon–carbon double bond. This analogue was prepared using microwave assisted ring closing metathesis (RCM) using the 2nd generation Grubbs as catalyst. Under our optimized conditions the cyclization between allylGly 3 and 14 proceeded in moderate yield, excellent cyclic/linear ratio and very high Z-double bond selectivity. NMR studies also demonstrated that the conformational flexibility of this peptide is increased in comparison to that of the natural hormone. Remarkably, this alkene-bridged somatostatin analog is highly selective against somatostatin receptors 1 and 5, suggesting that conformational rigidity is not required for the efficient interaction of somatostatin analogues with these two receptors.     

Synthesis and antiproliferative activity of some steroidal lactams

Using cholesterol as starting material, a series of 6-substituted-3-aza-A-homo-3-oxycholestanes and 6-substituted-4-aza-A-homo-3-oxycholestanes were synthesized by the oxidation, reduction, oximation, Beckman rearrangement and condensation reaction. These synthesized compounds displayed a distinct cytotoxicity against MGC 7901, HeLa and SMMC 7404 cancer cells. Our results revealed that the structures of functional groups at position-6 on the steroidal ring are crucial for the IC₅₀ value of antiproliferative activities of these compounds and the cytotoxic activity against MGC 7901 and SMMC 7404 cells was not significantly different between 4-N-lactams and 3-N-lactams when its 6-substituted group was a carbonyl or a hydroximino, but all 3-N-lactams showed a higher cytotoxicity against HeLa cells than 4-N-lactams. In particular, compounds 6, 8, 9 (IC₅₀6: 6.5 μmol/L; 8: 7.7 μmol/L; 9: 5.6 μmol/L) were even more cytotoxic than cisplatin to HeLa cells (positive contrast, 10.1 μmol/L). The information obtained from the studies may be useful for the design of novel chemotherapeutic drugs.