1. Synthesis and biological activity of novel amino acid-(N'-benzoyl) hydrazide and amino acid-(N'-nicotinoyl) hydrazide derivatives
Sherine N Khattab Molecules. 2005 Sep 30;10(9):1218-28. doi: 10.3390/10091218.
The coupling reaction of benzoic acid and nicotinic acid hydrazides with N- protected L-amino acids including valine, leucine, phenylalanine, glutamic acid and tyrosine is reported. The target compounds, N-Boc-amino acid-(N;-benzoyl)- and N- Boc-amino acid-(N;-nicotinoyl) hydrazides 5a-5e and 6a-6e were prepared in very high yields and purity using N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl- methylene]-N-methyl-methanaminium hexafluorophosphate N-oxide (HATU) as coupling reagent. The antimicrobial activity of the Cu and Cd complexes of the designed compounds was tested. The products were deprotected affording the corresponding amino acid-(N;-benzoyl) hydrazide hydrochloride salts (7a-7e) and amino acid-(N;- nicotinoyl) hydrazide hydrochloride salts (8a-8e). These compounds and their Cu and Cd complexes were also tested for their antimicrobial activity. Several compounds showed comparable activity to that of ampicillin against S. aureus and E. coli.
2. Kinetics of peptide synthesis studied by fluorescence of fluorophenyl esters
E A Permyakov, V N Medvedkin, L V Klimenko, Y V Mitin, S E Permyakov Jr Int J Pept Protein Res. 1994 Nov;44(5):472-6. doi: 10.1111/j.1399-3011.1994.tb00184.x.
The kinetics of the reaction of Boc-alanine-trifluorophenyl, Boc-alanine-tetrafluorophenyl, Boc-alanine-pentafluorophenyl, and Boc-alanine-p-chlorotetrafluorophenyl esters (BocAlaOTrf, BocAlaOTfp, BocAlaOPfp, and BocAlaTfc, respectively) with leucine amide and with valine methyl ester have been measured using changes in fluorophenyl chromophore emission at 375 nm. The kinetic data cannot be well fit with a simple second-order reaction scheme. Measurements of the reaction kinetics at different concentrations of the reagents showed that the expression for the reaction rate is V = kC(N)0.5C(AE)1.5, in which k is the reaction rate constant, CN is the concentration of either LeuNH2 or ValOCH3, and CAE is the concentration of the fluorophenyl ester. This reaction equation indicates a complex, probably chain-like, reaction mechanism. The order of reactivity for these active esters with ValOCH3 is BocAlaOTfc > BocAlaOPfp > BocAlaOTfp > BocAlaTrf. The apparent rate constant, k, for the reaction with LeuNH2 is higher than that for the reaction with ValOCH3.
3. Cyclosporin H is a potent and selective competitive antagonist of human basophil activation by N-formyl-methionyl-leucyl-phenylalanine
A de Paulis, A Ciccarelli, G de Crescenzo, R Cirillo, V Patella, G Marone J Allergy Clin Immunol. 1996 Jul;98(1):152-64. doi: 10.1016/s0091-6749(96)70237-3.
Background: Cyclosporin A (CsA) binds with high affinity to cyclophilin, a critical step in the molecular mechanism of action of cyclosporins, where cyclosporin H (CsH) has extremely low affinity for cyclophilin. CsH differs from CsA by the substitution of the L-methyl valine at position 11 with it D-isomer. Methods: We compared the effects of CsA and CsH on the release of performed (histamine) and de novo synthesized inflammatory mediators (peptide leukotriene C4) from peripheral blood basophils activated by N-formyl-methionyl-leucyl-phenylalanine (FMLP). Results: CsH (8 to 800 nmol/L) concentration-dependently inhibited histamine and leukotriene C4 release from purified and unpurified basophils activated by FMLP, whereas CsA (8 to 800 nmol/L) had little inhibitory effect on histamine release from basophils challenged with FMLP. Inhibition of histamine release from basophils challenged with FMLP was extremely rapid and was abolished by washing the cells (three times) before challenge. CsH (8 to 800 nmol/L) had no effect on the release of histamine caused by C5a, platelet activating factor, monocyte chemotactic activating factor, RANTES, IL-8, bryostatin 1, and phorbol myristate. Preincubation of basophils with granulocyte-macrophage colony-stimulating factor (30 and 100 pmol/L), but not IL-1 beta (30 and 100 ng/ml), concentration-dependently reversed the inhibitory effect of CsH on FMLP-induced histamine release. CsH competitively inhibited the effect of FMLP on histamine release from basophils. The dissociation constant (Kd) for the CsH-FMLP receptor complex was approximately 9 x 10(-8) mol/L, more than 10-fold lower than that (approximately equal to 1.3 x 10(-6) mol/L) of N-t-BOC-methionyl-L-leucyl-phenylalanine (BocMLP), a known formyl peptide receptor antagonist. CsH inhibited tritiated FMLP binding to human polymorphonuclear leukocytes with a concentration required to inhibit binding by 50% of approximately 5.4 x 10(-7) mol/L, whereas BocMLP was less potent with a concentration required to inhibit binding by 50% of approximately 9.1 x 10(-5) mol/L. Scatchard analysis revealed that the decreased tritiated FMLP binding caused by CsH was due to a decrease in the Bmax (0.22 +/- 0.04 nmol/L/5 x 10(6) cells vs 0.09 +/- 0.01 nmol/L/5 x 10(6) cells; p < 0.05), without a significant difference in the Kd (5.16 +/- 1.22 nmol/L vs 6.32 +/- 2.42 nmol/L; p = NS). Conclusion: CsH is a potent and selective inhibitor of mediator release from basophils induced by activation of the formyl peptide receptor; it acts by interfering with agonist binding to FMLP receptors.
