A new acylated cyclopentapeptide namely, Cyclo-( N(alpha)-dipicolinoyl)- bis-[ L-Leu-DL-Nval]- L-Lys OMe (5) was suggested and synthesized. The structural conception of 5 was rationalized by analogy to the structural features of some known cyclodepsipeptides exemplified by the antibiotic and DNA intercalator actinomycin D (NSC: 3053), the ionophore and anti-HIV enniatin B (NSC: 692895) and the ionophore and antibiotic valinomycin (NSC: 630175). The cyclopeptide 5 was chemically synthesized, starting from its linear tetrapeptide ester precursor 2 by coupling L-lysine methyl ester to the prepared tetrapeptide acid 3 or hydrazide 4 via the mixed anhydride or azide method, respectively. A cytotoxic activity (cell killing) in both breast (NCF7) and CNS (SF-268) cell lines NCI, USA) was realized for 5, while less active cytotoxic profile was determined for 2. Moreover, we have recently reported general ionophoric and sensor characteristics particularly, for Pb (II) ions for both 5 and 2. Correlation between the cytotoxic activity and the ionophoric potency is a matter of future investigations.
A series of macrocyclic pyrido-pentapeptide candidates 2–6 were synthesized by using N,N-bis-[1-carboxy-2-(benzyl)]-2,6-(diaminocarbonyl)pyridine 1a,b as starting material. Structures of the newly synthesized compounds were established by IR, 1H and 13C-NMR, and MS spectral data and elemental analysis. The in-vitro cytotoxicity activity was investigated for all compounds against MCF-7 and HepG-2 cell lines and the majority of the compounds showed potent anticancer activity against the tested cell lines in comparison with the reference drugs. Out of the macrocyclic pyrido-pentapeptide based compounds, 5c showed encouraging inhibitory activity on MCF-7 and HepG-2 cell lines with IC50 values 9.41 ± 1.25 and 7.53 ± 1.33 μM, respectively. Interestingly, 5c also demonstrated multitarget profile and excellent inhibitory activity towards VEGFR-2, CDK-2 and PDGFRβ kinases. Furthermore, molecular modeling studies of the compound 5c revealed its possible binding modes into the active sites of those kinases.
In continuation to our search for new amino acid and peptide based anti-inflammatory agents, the suggestion, synthesis, structure elucidation of some Nα -bis-dipicolinoyl amino acids, linear tetra and cyclic octa bridged peptides 1-9, of which four are new compounds 6-9, were herein realized. Accordingly, Nα -bis-dipicolinoyl-L-leucine methyl ester 1, the corresponding acid 2, its bis-DL-norvalyl methyl ester homologue 3, the acid 4 and hydrazide 5 analogues were conventionally prepared.The tetrachlorophthalic acid hydrazine conjugate 6, anisaldehyde hydrazone 7, the benzenetetracarboxylic acid and naphthalenetetracarboxylic acid bis-L-leucyl-DL-norvalyl cyclic octa bridged peptides 8 and 9 respectively, were newly synthesized via condensation of the hydrazide 5 with the corresponding aldehyde or anhydride.The chromatographic, IR, NMR and mass spectral analysis confirmed the identities of the synthesized compounds.Comparable to the two reference antiinflammatory drugs indomethacin® and voltaren® (100%), the determined antiinflammatory potency of the candidates (carrageenan® induced paw edema in rats) revealed a general significant activity (66 - 94%), except for the practically inactive 6 (∼1.5 % activity).In particular, the potency of the (Nα -dipicolinoyl)-bis-L-leucyl-DL-norvalyl anisaldehyde hydrazone 7 was of 94 and 87%, comparable to the reference drugs. However, 7 also showed 58% protection against ulcer formation, comparable to null for indomethacin®. Additionally, an acceptable acute toxicity was observed (LD50: 2833 mg/kg, comparable to 2700 and 2850 for indomethacin® and voltaren® respectively).
In continuation to our search for new chiral macrocyclic peptide-based anti-inflammatories, the suggestion, synthesis, structure elucidation of some Nalpha-bis-dipicolinoyl amino acids, linear, tetra and cyclic (penta and octa)-bridged peptides 3-10, were realized herein. The newly synthesized compounds showed potent anti-inflammatory activity with low toxicity (LD50) comparable to indomethacin and diclofenac as reference anti-inflammatory drugs.
To investigate the specificity of the urid~ne-d~phosphate-~-acetylmuramyl-~-alanyl-~-g~utamate: meso-2,6-diaminopimelate synthetase, various compounds mimicking more or less different parts of the UDP-MurNAc-1.-Ala-D-Glu substrate were prepared. Their size ranged from that of uridine or L-Ala-D-Glu to that of the whole nucleotide substrate. Chemical synthesis led to Nu-acyl-dipeptides, in which the acyl group mimicked the MurNAc moiety, and to glycopeptides MurNAc(a or P-Me)-L-Ala-u-Glu, in which the anomeric function is blocked. Partial degradation or chemical modification of the substrate UDP-MurNAc-L-Ala-D-Glu afforded : MurOHNAc-L-Alau-Glu, P'-MurNAc-L-Ala-Ii-Glu, and DDP-MurNAc-L-Ala-u-Glu (DDP = dihydrouridine-diphosphate). All these compounds were tested as substrates or (and) inhibitors of the reaction catalyzed by the A2pm-adding enzyme, which, after partial purification, was obtained in two active forms. Among the compounds tested as substrates, only DDP-MurNAc-L-Ala-D-Glu was a good one. The K , for this compound was 97 pM versus 55 pM for the natural substrate. Among the various compounds tested as inhibitors, only P'-MurNAc-L-Ala-D-Clu and MurNAc(a or P-Me)-L-Ala-u-Gh had a significant inhibitory effect at 1 mM. Apparently, no particular portion of the molecule is predominantly responsible for its recognition by the enzyme. In other words, multiple sites located over the whole molecule are required for a proper recognition and determine the high specificity of this activity. Therefore, to obtain efficient competitive inhibitors it is necessary to synthesize molecules very similar in size and structure to the natural substrate.The cytoplasmic steps of the biosynthesis of bacterial cell wall peptidoglycan involve a series of uridine nucleotide precursors including, in particular, UDP-N-acetylmuramic acid and UDP-MurNAc-peptides [ 11. These latter compounds are intermediates in the reaction sequence leading to the formation of UDP-MurNAc-pentapeptide from UDP-MurNAc by the stepwise addition of L-alanine, D-glUtamiC acid, generally diaminopimelic acid or L-lysine, and D-alanyl-D-alanine. Each step is catalysed by a particular synthetase, the specificity of which has been examined in a few instances [l]. One approach to the systematic study of the specificity of such enzymes is to prepare substrate analogues and to test them as substrates or (and) inhibitors. A better understanding of the specificity of these synthetases would in turn be useful for the design and synthesis of more specific inhibitors. Owing to the fact that the reactions these enzymes catalyse are only encountered Abbreviations. Aad, 2-aminoadipic acid; A2pm, 2,6-diaminopimelic acid; Bzi, benzylidene; Bzl, benzyl; H4furan, tetrahydrofuran; HPLC, high-performance liquid chromatography; DDP, dihydrouridine-.5'-diphosphate; Lac, lactyl; Me, methyl; Meb, methylbuturyl; MeOH, methanol; Mur, muramic acid; MurOH, muramicitol [2-amino-3-0-(~-1 -carboxyethyl)-2-deoxy-~-glucito1]; NAc, Nacetyl; Nps, 2-nitrophenylsulfenyl; Pr, propionyl; Su, 1 -suc...
4bA series of chiral linear carboxamide derivatives (2- 15) with an incorporated peptide linkage have been prepared via the coupling of 1-ethyl-1,4-dihydro-7-methyl-4-oxo-quinoline-3-carboxylic acid (nalidixic acid, 1) with appropriate amino acid methyl esters. Coupling of 1 with amino acid methyl esters gave the corresponding peptide methyl esters 2, which were hydrolyzed with methanolic sodium hydroxide to the corresponding acids 3. Hydrazinolysis of esters 2with hydrazine hydrate afforded the corresponding acid hydrazide derivatives 4. The latter compounds were coupled with appropriate aldehydes or acetophenone derivatives to afford the corresponding Schiff base derivatives 5 and 6, respectively. The hydrazide derivative was reacted with phenyl isothiocyanate or carbonyl derivatives to give the corresponding thiosemicarbazide 7 and compounds 8- 10, respectively. Also, 4b was treated with acid monoanhydrides to give the corresponding imide derivatives 11- 13. Finally, 4b was reacted with tetracarboxylic acid dianhydride derivatives to afford the corresponding diimido carboxamide derivatives 14 and 15
As important cancer therapeutic agents, macrocyclic peptides have recently drawn great attention, mainly because they are synthetically accessible and have lower toxicity towards normal cells. In the present work, we synthesized newly macrocyclic pyridoheptapeptide derivatives. The synthesized derivatives were characterized using standard chemical and spectroscopic analytical techniques, and their anticancer activities against human breast and hepatocellular cancer cells were investigated. Results showed that compounds 1a and 1b were the most effective against hepatocellular (HepG2) and breast (MCF-7) cancer cell lines, respectively.
In search for more potent, particularly less ulcerogenic gastritis that hopefully replace the universal NSAID "Diclofenac", (2-[(2,6-dichlorophenyl)amino]-phenylacetic acid, C.A.S. 15307-86-5), twelve new non-proteinogenic amino acid conjugates of the drug, namely that of sarcosine, beta-alanine, D-leucine and D-phenylalanine, were synthesized and biologically screened for their anti-inflammatory, analgesic and ulcerogenic activity in rats. "Diclofenac" amino acid esters (IIa-d), were synthesized via the corresponding HOSu or HOBt active esters. Alkaline hydrolysis (NaOH) followed by acidification (KHSO4) or thioamide formation (Lawsson's Reagent, C.A.S. 19172-47-5), afforded the corresponding free acids IIIa-d or the thioamides IVa-d respectively. Interestingly, in contrary to the parent "Diclofenac", the synthesized candidates (except IIId), were entirely nonulcerogenic in rats. Further, they considerably retained a generalized anti-phlogistic activity. The major "Diclofenac" irritating gastric side effect was thus eliminated. Particularly, the sarcosine conjugate IIa and its thiomimic IVa exhibit promising therapeutic perspectives.
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