Tuftsin analogs and their biological activity

Summary In this paper the literature data on the structure-activity relationship for the series of tuftsin analogs are summarized. Among others, the questions of the substitution of particular amino acid residues in different positions of the peptide chain, as well as the questions of shortening and lengthening of the peptide chain of tuftsin, are reviewed. The existing models of the biologically active conformation of tuftsin are also summarized.     

Evaluation of in vivo [corrected] biological activity of new agmatine analogs of growth hormone-releasing hormone (GH-RH)

The effects of agmatine analogs of growth hormone releasing hormone (GH-RH) were compared to GH-RH(1-29)-NH2 after intravenous (iv) and subcutaneous (sc) administration to pentobarbital-anesthetized male rats. After the iv injection, the analogs [desNH2-Tyr1,Ala15,Nle27] GH-RH(1-28)Agm (MZ-2-51); [desNH2-Tyr1,D-Lys12,Ala15,Nle27] GH-RH(1-28)Agm (MZ-2-57); [desNH2-Tyr1,Ala15,D-Lys21,Nle27] GH-RH(1-28)Agm (MZ-2-75) and [desNH2-Tyr1, D-Lys12,21, Ala15, Nle27] GH-RH(1-28)Agm (MZ-2-87) showed a potency equivalent to 4.4, 1.9, 1.07 and 1.03 times that of GH-RH (1-29)-NH2, respectively, at 5 min and 5.6, 1.8, 1.9 and 1.8 times higher, respectively, at 15 min. After sc administration, analogs MZ-2-51, MZ-2-57 and MZ-2-75 showed to be 34.3, 14.3 and 10.5 times more potent than the parent hormone at 15 min and 179.1, 88.9 and 45.0 times more active, respectively, at 30 min. In addition, MZ-2-51 had prolonged GH-releasing activity as compared to the standard. We also compared the activity of MZ-2-51 and MZ-2-57 with their homologous L-Arg and D-Arg analogs [desNH2-Tyr1,Ala15,Nle27] GH-RH(1-29)-NH2 (MZ-2-117), [des-NH2Tyr1,D-Lys12, Ala15, Nle27] GH-RH(1-29)NH2 (MZ-2-123) and [desNH2-Tyr1,D-Lys12,Ala15, Nle27,D-Arg29] GH-RH(1-29)NH2 (MZ-2-135) after intramuscular (im) injection. MZ-2-51 induced a somewhat greater GH release than MZ-2-117 at 15 min, both responses being larger than the controls (p less than 0.01) at 15 and 30 min. MZ-2-57, MZ-2-123 and MZ-2-135 given i.m. were able to stimulate GH release only at 15 minutes (p less than 0.05). Animals injected i.m. with MZ-2-51, but not with MZ-2-117, showed GH levels significantly higher than the control group (p less than 0.05) at 60 min. GH-RH(1-29)NH2 had low activity intramuscularly when tested at a dose of 2.5 micrograms. No toxic effects were observed after the iv administration of 1 mg/kg of Agm GH-RH analogs. These results indicate that our Agm analogs are active iv, sc and im and that the substitutions made in these compounds produce increased and prolonged GH releasing activity. These analogs, especially MZ-2-51, should be useful for clinical and veterinary purposes.     

Biological activity of synthetic analogs of serum thymic factor

A series of analogs of serum thymic factor (Facteur Thymique Sérique; FTS) devoid of C- and N-terminal few residues were synthesized and their ability to induce Thy-l (theta) antigen in vitro on mouse T lymphocyte precursors was examined. The pentapeptide moiety (Lys-Ser-Gln-Gly-Gly) seems to be important for the expression of agonistic activity. Some of the short chain peptides showed antagonistic properties. Synergistic activation by two inactive analogs was observed.     

biological activity of phosphorus analogs of amino acids

Data available in literature on biological activity of the phosphorus analogues of amino acids are summarized. The most typical kinds of bioactivity of aminophosphonic, aminophosphinic and aminophosphonous acids are characterized. These compounds, both natural and synthetic, are shown to possess a wide spectrum of bioactivity and may be estimated as potential bioregulators.     

Fungicidal activity of natural and synthetic sesquiterpene lactone analogs

Fungicidal activity of 36 natural and synthetic sesquiterpene lactones with guaianolide, trans, trans-germacranolide, cis, cis-germacranolide, melampolide, and eudesmanolide carbon skeletons was evaluated against the phytopathogenic fungi Colletotrichum acutatum, C. fragariae, C. gloeosporioides, Fusarium oxysporum, Botrytis cinerea, and Phomopsis sp. Dose-response data for the active compounds dehydrozaluzanin C, dehydrocostuslactone, 5alpha-hydroxydehydrocostuslacone, costunolide, and zaluzanin C are presented. A new 96-well microbioassay procedure for fast and easy evaluation of antifungal activity was used to compare these compounds with commercial fungicide standards. Some structure-activity conclusions are also presented.     

Synthesis and biological activities of marine terpene-adenine hybrids and synthetic analogs

Marine sponges (Agelas sp., Raspailia sp.) produce bioactive metabolites, which can be regarded as hybrids between a terpenoid and an adenine derivative. Three sub classes are known: Agelasines, agelasimines and asmarines. Currently 19 agelasines or closely related structures, two agelasimines and 11 asmarines are published. The two agelasimines have been prepared by total synthesis, the same is true for some of the agelasines, but none of the asmarines have been synthesized so far. Agelasines are associated with antimicrobial and antineoplastic activities. Several analogs have been prepared, which are even more potent than the naturally occurring compounds, and interesting leads for treatment of for instance tuberculosis, Chagas disease and leishmaniasis have been identified. Also antifouling agents and biofilm inhibitors have been found among agelasines and analogs. Agelasines inhibits Na,K-ATPase and other ATPases, but how relevant this is for their mechanism of action, as antimicrobial and antineoplastic agents, are currently poorly understood. Agelasimines A and B display antineoplastic activity and they have the ability to inhibit smooth muscle contraction. Synthetic analogs with both antimicrobial and anticancer activities are known. Biological activities of asmarines are far less studied than those of agelasines and agelasimines, but some of them are claimed to be cytotoxic compounds.     

Antiretroviral activity of synthetic hypericin and related analogs.

Hypericin and pseudohypericin are naturally occurring polycyclic quinones which have recently been shown to inhibit the infectivity of several retroviruses, including human immunodeficiency virus. To better understand the antiviral mechanisms of these compounds, hypericin and a series of analogous quinones were synthesized and tested for anti-retroviral activity against equine infectious anemia virus (EIAV). Treatment of EIAV-infected cells with hypericin reduced the production of infectious virus by 99.99%. None of the analogs were found to inhibit virus replication. These results suggest that the complete ring structure of hypericin is required, but not sufficient, for antiviral activity.     

Evaluation of the antiviral activity of natural sulfated polyhydroxysteroids and their synthetic derivatives and analogs.

Disodium 3beta,21-dihydroxypregn-5-en-20-one disulfate (2), sodium 3beta,21-dihydroxypregn-5-en-20-one 3-sulfate (3), sodium 3beta,21-dihydroxypregn-5-en-20-one 21-sulfate (4), and disodium 3beta,6alpha-dihydroxy-5alpha-pregnan-20-one disulfate (6) have been synthesized and completely characterized for the first time from readily available materials. Sulfation was performed using triethylamine-sulfur trioxide complex in dimethylformamide as the sulfating agent. Selective sulfation of 3beta,21-dihydroxypregn-5-en-20-one rendered sodium 3beta,21-dihydroxypregn-5-en-20-one 3-sulfate (3) as the major compound. The synthetic sulfated steroids as well as natural disulfated polyhydroxysteroids (7-9) isolated by us from the antarctic ophiuroid Astrotoma agassizii and the synthetic derivatives disodium 2beta,3alpha,21-trihydroxy-(20R)-cholesta-5,24-diene 3-acetate, 2,21-disulfate (7a) and 2beta,3alpha,21-trihydroxy-(20R)-cholesta-5,24-diene (7b) were comparatively evaluated for their inhibitory effect on the replication of one DNA (HSV-2) and two RNA (PV-3, JV) viruses. In general, steroids with sulfate groups at C-21 and C-2 or C-3 were the most effective in their inhibitory action against HSV-2 and also proved to be active against PV-3 and JV.     

Synthesis and biological activity of brassinolide analogues, 26,27-bisnorbrassinolide and its 6-oxo analogue

Two hitherto unknown brassinolide analogues, (22R,23R)-2α,3α,22,23-tetrahydroxy-B-homo-7-oxa-24-nor-5α-cholestan-6-one (9b) and (22R,23R)-2α,3α,22,23-tetrahydroxy-24-nor-5α-cholestan-6-one (8a), were stereoselectively synthesized. In both the Raphanus and rice-lamina inclination tests, 9b exhibited almost the same activity as brassinolide (1) and 8a also showed ca 10–50% of the activity of 1.     

Semi-synthesis and biological activity of gamma-lactones analogs of camptothecin

A series of E-ring gamma-lactone camptothecin derivatives were synthesized by semi-synthesis via a three-step domino reaction. Their biological activity was evaluated on two types of human tumor cell lines A549 and HT-29 with sulforhodamine-B (SRB) method. The antitumor activity of these compounds was lower than SN-38, only compound 12c was found to be close to the activity of Topotecan. The structure-activity relationship (SAR) of these analogs was studied and discussed.     

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.     

CNS and antimalarial activity of synthetic meridianin and psammopemmin analogs

The marine invertebrate-derived meridianin A, the originally proposed structure for psammopemmin A, and several related 3-pyrimidylindole analogs were synthesized and subsequently investigated for central nervous system, antimalarial, and cytotoxic activity. A Suzuki coupling of an indoleborate ester to the pyrimidine electrophile was utilized to form the natural product and derivatives thereof. The 3-pyrimidineindoles were found to prevent radioligand binding to several CNS receptors and transporters, most notably, serotonin receptors (<0.2 μM K(i) for 5HT(2B)). Two compounds also inhibited the human malaria parasite Plasmodium falciparum (IC(50) <50 μM). Only the natural product was cytotoxic toward A549 cells (IC(50)=15 μM).     

Conformationally constrained chemotactic peptide analogs of high biological activity

The stereochemically constrained chemotactic peptide analogs, formylmethionyl-alpha-aminoisobutyryl-phenylalanine (formyl-Met-Aib-Phe-OH) and formylmethionylcycloleucinylphenylalanine (formyl-Met-Cyl-Phe-OH) are highly effective in inducing lysosomal enzyme release from rabbit neutrophils. NMR studies of the Aib2 analog in (CD3)2SO favor a folded conformation in which the Phe NH group is inaccessible to solvent. Intramolecularly hydrogen-bonded conformations involving a Met-Aib-beta-turn or a gamma-turn centered at Aib2 are considered. The results suggest that folded conformations may allow highly active interactions with the neutrophil formylpeptide receptor.     

Evaluation of synthetic sphingolipid analogs as ligands for peroxisome proliferator-activated receptors

In this Letter, we assessed newly synthesized sphingolipid analogs as ligands for peroxisome proliferator-activated receptor (PPAR)α, PPARβ or PPARγ, using a dual-luciferase reporter system. We tested 640 sphingolipid analogs for ligand activity. As a result, seven types: A9, B9, C9, C50, F66, G66 and H66, were found to show agonistic activities for PPARs.     

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.     

Evaluation of the biological potency of new agmatine analogs of growth hormone-releasing hormone in the bovine.

Four new growth hormone-releasing hormone (GHRH) analogs with C-terminal agmatine were compared with the parent human GHRH(1-29)NH2 fragment to assess their abilities to increase serum concentrations of growth hormone (GH) in the bovine. The four analogs were: [D-Ala2, Nle27] GHRH(1-28)Agm (JG-73); [desNH2-Tyr1, Ala15, Nle27] GHRH(1-28)Agm (MZ-2-51); [desNH2-Tyr1, Ala15, D-Lys21, Nle27] GHRH(1-28)Agm (MZ-2-75); and [desNH2-Tyr1, D-Lys12,21, Ala15, Nle27] GHRH(1-28)Agm (MZ-2-87). The special characteristic of all four GHRH analogs is that arginine was replaced by agmatine (Agm) in Position 29. Five pregnant Holstein cows received these peptides subcutaneously at the following doses: 0.0156, 0.0625, 0.25, 1, and 4 micrograms/kg body wt. Each cow received each analog-dose combination according to a 5 x 5 Greco-Latin square design repeated for the 5-week treatment. Each cow also received saline vehicle only at the end of the 5-week treatment. Blood samples were collected from 30 min before until 360 min after treatment injection. Total area under the GH response curves for the 6-hr sampling period for each dose of each GHRH analog was compared. There was a linear dose-dependent GH release in response to hGHRH(1-29)NH2 and its four GHRH(1-28)Agm analogs. At the dose of 0.25 micrograms/kg, two GHRH analogs, JG-73 and MZ-2-75, stimulated greater GH release than hGHRH(1-29)NH2 (P less than 0.05). No differences were seen at the two lowest doses, 0.0625 and 0.156 micrograms/kg. When both total area under the GH response curves and GH peak amplitudes for each treatment were averaged for all doses, JG-73 and MZ-2-75 stimulated greater GH release than hGHRH(1-29)NH2 (P less than 0.05). In summary, three GHRH(1-28)Agm analogs, JG-73, MZ-2-75, and MZ-2-51, were found to be 11.8, 11.3, and 6.5 times more potent, respectively, on a weight basis, than hGHRH(1-29)NH2 in stimulating the release of GH in cows.     

Human follicular gonadotropin releasing peptide analogs. Evaluation of biological (in vitro) and immunological activity

Human follicular gonadotropin releasing peptide (hF-GRP) has been shown to stimulate pituitary LH and FSH secretion in vitro. Six hF-GRP analogs have been synthesized and evaluated for gonadotropin releasing activity in a rat anterior pituitary primary cell culture system. A tyrosine analog of hF-GRP, [Tyr4]-hF-GRP, retained comparable biological activity in releasing gonadotropins. However, acetylation of hF-GRP in Ac-hF-GRP greatly reduced the in vitro activity. The shorter segments of hF-GRP, hF-GRP-(5-14), and hF-GRP-(10-14), were tested for LH and FSH releasing activity, and it was found that the decapeptide retained moderate activity while the activity of the pentapeptide was markedly lower than hF-GRP. The baboon alpha 1 antitrypsin-(27-40) peptide, b-alpha 1 AT-(27-40), is relatively less potent in releasing LH than hF-GRP. Interestingly, the baboon peptide is more potent (2.5-fold) in releasing FSH under identical conditions. The effect of hF-GRP in releasing LH and FSH was not affected by the presence of LHRH antagonists in cell culture systems. When these peptides were tested for immunological activity in a hF-GRP radioimmunoassay, it was found that hF-GRP and [Tyr4]-hF-GRP have comparable activities. The C-terminal decapeptide of hF-GRP is more active (1.5-fold) in the RIA, and the C-terminal pentapeptide had only one third of the immunoreactivity. The b-alpha 1-AT-(27-40) failed to cross-react in the RIA even at a concentration of 20 micrograms per tube.