New conjugates of muramyl dipeptide and nor-muramyl dipeptide linked to tuftsin and retro-tuftsin derivatives significantly influence their biological activity

The synthesis and biological activity of new conjugates of muramyl dipeptide (MDP) and nor-muramyl dipeptide (nor-MDP) with tuftsin and retro-tuftsin derivatives containing isopeptide bond between ε-amino group of lysine and carboxyl group of simple amino acids such as Ala, Gly and Val are presented. We presumed, based on the cytokine profile, that the examined conjugates of tuftsin and MDP were capable of activating antibacterial mechanisms by switching on Th1 immune response. The most active were compounds 11, 14 and 19-23.     

Synthesis and biological evaluation of andrographolide derivatives as potent anti-HIV agents

In an attempt to develop potent anti-HIV drugs, 20 andrographolide derivatives were designed, synthesized, and evaluated for their in vitro anti-HIV activity. The screening results revealed that five compounds showed potent anti-HIV activities with therapeutic indices (TI) above 10. The most promising compound 6f shows a significant TI close to 34.07, with the potency to be a new lead.     

Synthesis,radiolabelling and biological evaluation of terminal oxamide derivatives of mercaptoacetyltriglycine

^99mTc‐MAG₃ is widely used in clinical nuclear medicine as a potential replacement of ¹³¹I‐OIH for renal function studies. The terminal carbonylglycine in the MAG₃ backbone is assumed to be essential for maintaining its efficient renal handling characteristics. A number of MAG₃‐derivatives have been prepared and evaluated in which the terminal carbonylglycine sequence is substituted by an oxamide moiety in order to study the effect of the modified carbonylglycine sequence on the renal handling characteristics. These ‘oxamide’ derivatives have been synthesized starting from mercaptoacetic acid or cysteamine using the common synthetic procedures of peptide chemistry. These thiol‐protected MAG₃‐precursors were labelled with ^99mTc by an exchange method using tartrate as a complexing agent. Biodistribution studies in mice showed that some of these agents were cleared rapidly from the blood and efficiently excreted into the urine and displayed comparable renal excretion characteristics to those of ^99mTc‐MAG₃. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis and biological evaluation of novel flavanone derivatives as potential antipsychotic agents

In this study, a series of novel flavanone derivatives were designed and synthesized, and the antipsychotic activities of the target compounds were evaluated in vitro and in vivo. The results showed that synthesized compounds 7a – 7g decreased the activity of dopamine D₂ receptors in HEK293 cells co‐transfected with D₂ receptor/G protein α16a, with IC₅₀ values of 0.051–0.35 μm . Compounds 7a – 7g inhibited the over‐production of nitric oxide stimulated by lipopolysaccharide/interferon‐γ in BV‐2 microglial cells. In mice, intragastric administration of 7d , 7e , and 7g reversed the increase in locomotor activity induced by MK‐801 (an antagonist of NMDA receptors) and decreased the hyperactivity of climbing behavior induced by apomorphine (a dopamine receptor agonist). These results suggest that some of the novel flavanone derivatives have potential antipsychotic effects and may be useful in the treatment of schizophrenia.     

Synthesis and antibacterial action of cecropin and proline-arginine-rich peptides from pig intestine

Dedicated to Professor Koji Nakanishi on the occasion of his 70th birthday. Two antimicrobial peptides, cecropin P1 (CPl), with a C-terminal carboxyl group, and PR-39, with an amidated C-terminus, are found in the small intestine of the pig. Each is active against both Gram-positive and Gram-negative bacteria. We have synthesized these peptides and several analogs, including the d -enantiomers and the retro sequences, each with a free or acetylated amino terminus. The CPI amide was also prepared. The retro CP1 peptides were much less active than the parent CPl peptide, confirming the importance of sequence or the amide bond and helix dipole direction, and the N^α-acetyl peptides were also less active, indicating that a free amino terminus is essential for high activity. The ratio of the lethal concentration of L/D isomers of CP1 is less than 1 for Gram-negative, but greater than 1 for Gram-positive bacteria. PR-39 showed no significant chiral selectivity toward Escherichia coli, Bacillus subtilis and Streptococcus pyogenes, but the l /d ratio was high for Pseudomonas aeruginosa (66), and very high for Staphylococcus aureus (>1000). In the latter case the lethal concentration for the d -isomer was 0.57 μ whereas this organism was quite resistant to the l -isomer (>600μ). Thus the enantiomers of CP1 and PR-39 are not equally active for all species. In a plate assay with a very small log-phase inoculum of Staph. aureus, D-PR-39 produced a clear zone of killing surrounded by a zone of stimulated growth. After prolonged incubation the two zones became one clear zone. Addition of D-PR-39 to the wells of a dense turbid plate of growing cells showed a cleared zone for each of the test organisms, indicating that PR-39 lyses the bacteria rather than simply inhibiting their multiplication. © Munksgaard 1997.     

Synthesis and immunological evaluation of the conjugates composed from a muramyl peptide GMDP and tuftsin

The conjugates of a muramyl dipeptide analog GMDP (N-acetylglucosaminyl β1→4 N-acetylmuramyl-L-alanyl-D-isoglutamine) and tuftsin (Thr-Lys-Pro-Arg) were synthesized from unprotected GMDP by mixed anhydride procedure. The identity of the conjugates was confirmed by high resolution NMR and their immunomodulating properties were determined in various tests. It was found that the conjugate in which the GMDP carboxyl group forms an amide bond with the &-amino group of tuftsin lysyl residue exceeds GMDP in all the activities determined. Synergism of GMDP and tuftsin was found in phagocytosis stimulation assay.     

Synthesis and cytotoxic evaluation of some new phthalazinylpiperazine derivatives

A new series of 1,4‐disubstituted phthalazinylpiperazine derivatives 7a–f , 12a–f and 20a–f were designed and synthesized in order to develop potent and selective antitumor agents. The target compounds were screened for their cytotoxic activities against A549, HT‐29 and MDA‐MB‐231 cancer cell lines in vitro. Among them, compounds 7a–f exhibited excellent selectivity for MDA‐MB‐231 with IC₅₀ values ranging from 0.013 µM to 0.079 µM. The most promising compound, 7e (IC₅₀ = 2.19 µM, 2.19 µM, 0.013 µM), was 9.3, 10, and 4.9 × 10³ times more active than vatalanib (IC₅₀ = 20.27 µM, 21.96 µM, 63.90 µM), respectively.     

Effect of Huangqin decoction on regulating intestinal flora in colitis mice characterized as inhibition of the NOD2-dependent pathway

ContextChinese herb Huangqin decoction (HQD) can regulate intestinal flora in ulcerative colitis (UC) mice.ObjectiveOur study clarifies the mechanism of HQD in regulating the intestinal flora of UC mice.Materials and methodsMale C57BL/6 mice were randomly divided into six groups: Control, Model (3% DSS), Sulfasalazine (500 mg/kg), HQD-L (250 mg/kg), HQD-M (500 mg/kg), and HQD-H (1000 mg/kg) groups. Measurement of body weight, colon length, DAI, and haematoxylin–eosin staining were conducted. FISH and 16S rDNA detected colonic bacterial infiltration and intestinal flora changes. The expression of RegIIIγ and PRRs (NOD2, TLR5, TLR4) were detected by FCM and WB, respectively. In addition, WB, qPCR, or IHC were used to detect the expression of NOD2, MyD88, RIP2, and NF-κB p65 in the colon. ELISA was used to determine cytokines.ResultsCompared with the model group (DAI score, 2.38 ± 0.05; histological score, 4.08 ± 0.54), HQD treatment significantly reduced the DAI score (L, 2.16 ± 0.09; M, 1.45 ± 0.05; H, 1.18 ± 0.05) and histological score (L, 3.16 ± 0.82; M, 2.50 ± 0.81; H, 1.51 ± 0.76); restored the weight, the colonic length (p < 0.05). 16S rDNA identification showed HQD regulated the balance of intestinal flora. Moreover, HQD suppressed the expression of RegIIIγ (p < 0.05) and prevented colonic bacterial infiltration. Furthermore, WB results showed NOD2, and TLR4 were inhibited by HQD, especially NOD2 (p < 0.01). The data of WB, qPCR, and IHC demonstrated that the NOD2-dependent pathway was inhibited by HQD (p < 0.01).Discussion and conclusionsHQD (1000 mg/kg) regulates the intestinal flora of colitis mice, mainly characterized as inhibition of the NOD2-dependent pathway. These results indicate that HQD has potential.     

Synthesis and biological evaluation of novel peptides based on antimicrobial peptides as potential agents with antitumor and multidrug resistance‐reversing activities

Tumor chemotherapy, which plays an important role in the clinical treatment of metastatic cancer, is limited by low selectivity and drug resistance in clinical application. In our study, we selected antimicrobial peptide BP100 as a lead peptide, designed, and synthesized a series of novel antineoplastic peptides through solid‐phase synthesis. Among them, B4 and B8 showed excellent anticancer activity. As revealed by further investigations, these peptides could disrupt the cell membrane, trigger the cytochrome C release into cytoplasm, and ultimately lead to apoptosis. In addition, they also showed multidrug resistance‐reversing effects by performing effective antitumor activity against multidrug‐resistant cells. As a result, these peptides may possibly be regarded as a promising candidate for cancer treatment.     

Synthesis and biological evaluation of resveratrol derivatives with anti-breast cancer activity

Resveratrol is a natural phytoestrogen produced by plants to protect themselves from injury, UV irradiation, and fungal attack. The main active structure is E-resveratrol, which has many pharmacological activities. As the structure of resveratrol is similar to the natural estrogen 17β-estradiol and the synthetic estrogen E-diethylstilbestrol, resveratrol is used in reducing the incidence of breast cancer. However, the therapeutic application of resveratrol is limited due to its low bioavailability. To improve its bioavailability and pharmacological activity, some resveratrol derivatives have been designed and synthesized by substitutions of methoxy, hydroxyl, and other functional groups or heterocyclic esterification either on the “A” or “B” ring, and double bonds were replaced by imine bonds and isometric heterocycles such as naphthyl and imidazole, or synthetic resveratrol oligomers. The structures, synthetic routes, and evaluation of the biological activities of these compounds are discussed. These are aimed at providing some references for the study of resveratrol derivatives in anti-breast cancer treatment.     

Synthesis and biological evaluation of pseudolaric acid B derivatives as potential immunosuppressive agents

Pseudolaric acid B (PB) derivatives with immunosuppressive activity were found by our group. In order to find potential immunosuppressive agents with high efficacy and low toxicity, a series of novel PB derivatives were synthesized and evaluated on their immunosuppressive activities. Most of the synthesized compounds were tested in vitro on murine T and B proliferation. In particular, compound 11 exhibited excellent inhibitory activity toward murine T cells (up to 19-fold enhancement compared to that of mycophenolatemofetil) and little cytotoxicity toward normal murine spleen cells. These experimental data demonstrated that some of these PB derivatives have great potential for future immunosuppressive studies.     

Synthesis and biological evaluation of new quinoxaline derivatives as antioxidant and anti-inflammatory agents

We report the synthesis, anti-inflammatory, and antioxidant activities of novel quinoxaline and quinoxaline 1,4-di-N-oxide derivatives. Microwave-assisted methods have been used to optimize reaction times and to improve yields. The tested compounds presented important scavenging activities and promising in vitro inhibition of soybean lipoxygenase (LOX). Two of the best LOX inhibitors (compounds 7b and 8f) were evaluated as in vivo anti-inflammatory agents using the carrageenin-induced edema model. One of them (compound 7b) showed important in vivo anti-inflammatory effect (41%) similar to that of indomethacin (47%) used as the reference drug.     

Synthesis and biological evaluation of (--)-linarinic acid derivatives as neuroprotective agents against OGD-induced cell damage

A series of novel (-)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-1-carboxylic acid derivatives were designed and synthesized. All of the prepared compounds were screened for their neuroprotective effects using an in vitro oxygen glucose deprivation (OGD) model of ischemic stroke. Some of the target compounds exhibited moderate to excellent protective potency. In particular, compounds 9d, 9e, 9g, and 9h showed significant protective effects in the SH-SY(5) Y cell line at all three concentrations tested.     

Synthesis and cytotoxicity evaluation of novel podophyllotoxin derivatives

Seven benzylamino derivatives of podophyllotoxin 8a–8g were synthesized and their chemical structures were confirmed by IR, ¹H‐NMR, ¹³C‐NMR and ESI‐MS spectral analyses. Their abilities to inhibit the growth of cancer cells A549, HCT‐116 and HepG2, were investigated by MTT assay. Compound 8b possessed the highest cytotoxicity on cancer cell lines with average IC₅₀ values of 3.8 µM. All we synthetic compounds were cytotoxic against three cancer cell lines at the micromolar range, indicating podophyllotoxin derivatives with structural modification of benzylamino possess potent antitumor activity.     

Synthesis and in-vivo evaluation of carbonyl-amide linkage based new benzimidazole derivatives

In search of pharmacologically active potent compounds, a series of carbonyl-amide linkage based new benzimidazole derivatives were synthesized from acid, aldehydes and isocyanide at ambient temperature via Passerini reaction. All the compounds synthesized were screened for their potential anti-inflammatory, antidiabetic and anticonvulsant properties. The results revealed that compounds 2i and 2j were found to be the most potent anti-inflammatory agents, while compounds 2a, 2c, 2e, 2f, 2i and 2j showed increased antidiabetic activity than the reference drugs and 2a, 2g, 2h, 2i and 2j were found to be the main structural requirement for maintaining anticonvulsant activity.     

Design,synthesis, and biological evaluation of novel tetrahydroisoquinoline derivatives as potential antitumor candidate

A novel class of tetrahydroisoquinoline derivatives was designed and synthesized as antitumor agents and evaluated for their in vitro and in vivo biological activities. The antiproliferative activities of all the target compounds on HUVEC, MCF‐7, and HT‐29 were evaluated. Compared with colchicine (1.04 × 10^?2 μm ), 17d and 17e exhibited outstanding activity on MCF‐7 with IC₅₀ values 0.26 × 10^?2 μm and 0.89 × 10^?3μm in cell cytotoxicity assay. The tubulin polymerization assay demonstrated that 17d and 17e exhibited better inhibition rate. In the MCF‐7‐xenograft mouse model that was treated with 17d and 17e by intraperitoneal injection, the tumor weight was decreased at same rate with tamoxifen, and relative tumor proliferation rates were 59.48% and 41.33%, while tamoxifen was 45.08% with a daily dose of 20 mg/kg, which were demonstrated potent in vivo efficacy.     

Synthesis of bis‐ and tris‐branched COOH‐terminal pegylating reagents: conjugation to NH2‐terminal peptides

Abstract: In previous studies we reported an orthogonal protection scheme that was developed for the solution‐phase synthesis of a family of bis‐ and tris‐pegylating reagents which contain a free NH₂‐terminus. These pegylating reagents were coupled to the COOH‐terminus of a model peptide. In the present study we report on the solution synthesis of a novel family of bis‐ and tris‐pegylating reagents which contain a free COOH‐terminus. To illustrate their general utility, conditions were developed for the coupling of these novel pegylating reagents to the NH₂‐function of a model pentapeptide. Taken together, our studies demonstrate that these pegylating reagents are well suited for conjugation to peptides and proteins that contain either free COOH‐ or NH₂‐functions. These reagents may have general utility in therapeutic development as branched pegylation has been shown to provide more effective protection of proteins from proteolysis by shielding the protein surface from approaching macromolecules.     

4,5-Diaryl-3-aminopyrazole derivatives as analogs of Combretastatin A-4: synthesis and biological evaluation

A series of cis-restricted 4,5-diaryl-3-aminopyrazole derivatives were synthesized and tested for their cytotoxic activity in vitro against five human cancer cell lines (K562, ECA-109, A549, SMMC-7721, and PC-3). Compounds 5a, 5b, 5d, and 6b showed potent cytotoxicity against all tested cell lines. Primary mechanism research on compound 5a indicated that it was a potent inhibitor of tubulin polymerization, arresting cell cycle in G(2)/M phase. The docking research showed the conformation of 5a overlaps well with CA-4 in the crystallized protein complex, suggesting the 4,5-diaryl-3-aminopyrazoles were good mimics of CA-4.     

Synthesis and biological evaluation of some hydroxypyrazole derivatives as anti-inflammatory-antimicrobial agents

Some hydroxypyrazole derivatives 2-7 were synthesized by cyclocondensation of the keto-ester 1 with hydrazines hydrate or substituted hydrazines followed by reduction and acylation with acetic anhydride or trifluoroacetic anhydride. The newly synthesized compounds were evaluated for their anti-inflammatory, antimicrobial activities. In addition, the ulcerogenic and acute toxicity profiles were determined. Compounds N-(4-(5-hydroxy-1-trifluoroacetyl-1H-pyrazol-3-yl)phenyl) trifluoroacetamide 4b, 3-(4-nitrophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-ol 5b, and N-(4-(5-hydroxy-1-methyl-1H-pyrazol-3-yl)phenyl)trifluoroacetamide 7b were proved to be the most active anti-inflammatory, antimicrobial agents in the present study with a good safety margin and minimal or no ulcerogenic effect.