ABSTRACT
Dimeric cinnamoylamide derivatives were synthetized and tested as inhibitors of tyrosinase activity and melanin formation. The most active dimeric cinnamoylamide derivatives was dimeric compound of p-coumaric acid (compound 1) that inhibited tyrosinase activity more efficiently than p-coumaric acid. It also inhibited melanin production by B16 melanoma cell line and normal human melanocytes more efficiently than kojic acid. We next investigated the potential mutagenic and skin sensitization effect of compound 1. Compound 1 was found to induce no mutagenic activity, no irritation and no delayed contact hypersensitivity at the maximum concentration of 10%. In vitro percutaneous absorption studies exhibited that compound 1 could diffuse across the skin till its site of action. All these results lead us to propose that compound 1 may be a safe and effective candidate for treating skin hyperpigmentation related disorders.
Subject(s)
Coumaric Acids/pharmacology , Dermatologic Agents/pharmacology , Ethylenediamines/pharmacology , Hyperpigmentation/drug therapy , Melanins/biosynthesis , Melanocytes/drug effects , Monophenol Monooxygenase/antagonists & inhibitors , Skin Diseases/drug therapy , Animals , Cell Line , Cell Line, Tumor , Coumaric Acids/chemical synthesis , Coumaric Acids/therapeutic use , Dermatologic Agents/chemical synthesis , Dermatologic Agents/therapeutic use , Dimerization , Ethylenediamines/chemical synthesis , Ethylenediamines/therapeutic use , Humans , Hyperpigmentation/metabolism , Melanocytes/metabolism , Melanoma, Experimental/metabolism , Mice , Pyrones/pharmacology , Skin Absorption , Skin Diseases/metabolismABSTRACT
Increased production and accumulation of melanin lead to hyperpigmentation disorders. Several inhibitors of tyrosinase, the key enzyme in melanin synthesis have been developed but exhibited lack of efficiency or some adverse side effects. Therefore, it appears very important to find new agents that will be able to promote inhibition of tyrosinase and pigmentation. In this study, some phenylalkylcinnamide molecules were synthesized and evaluated for their ability to act as tyrosinase inhibitors. Compounds 2 (IC(50)=0.03 mM) and 12 (IC(50)=0.028 mM) showed strong tyrosinase inhibitory potential comparable to standard hydroquinone (IC(50)=0.037 mM). Taken together, compounds 2 and 12 can be considered as good candidates for further investigations to evaluate their effect on the inhibition of melanin synthesis and skin pigmentation.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Benzene Derivatives/chemical synthesis , Benzene Derivatives/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Monophenol Monooxygenase/antagonists & inhibitors , Agaricales/enzymology , Cinnamates/chemistry , Hydroquinones/pharmacology , Structure-Activity RelationshipABSTRACT
A series of N-hydroxy-N'-phenylthiourea and N-hydroxy-N'-phenylurea analogues were prepared and evaluated as inhibitors of tyrosinase and melanin formation. The most active analogue 1 inhibited mushroom tyrosinase with an IC(50) of around 0.29 microM and also retained a substantial potency in cell culture by reducing pigment synthesis by 78%. Therefore, compound 1 could be considered as a promising candidate for preclinical drug development for skin hyperpigmentation application.
Subject(s)
Melanins/antagonists & inhibitors , Melanocytes/drug effects , Monophenol Monooxygenase/drug effects , Peptides/pharmacology , Phenylthiourea/analogs & derivatives , Phenylthiourea/pharmacology , Agaricales/enzymology , Animals , Cell Line, Tumor , Dose-Response Relationship, Drug , Inhibitory Concentration 50 , Melanins/biosynthesis , Melanocytes/enzymology , Melanoma , Mice , Molecular Structure , Monophenol Monooxygenase/chemistry , Peptides/chemical synthesis , Peptides/chemistry , Phenylthiourea/chemistry , Stereoisomerism , Structure-Activity Relationship , Toxicity TestsABSTRACT
Gamma9delta2T cells represent the most abundant population of human blood gammadeltaT lymphocytes. They produce and promote strong cytotoxic activity against many pathogens that are implicated in several human infectious diseases. Their activation requires their exposure to small phosphorus-containing antigens in the family of prenyl pyrophosphates and their related biosynthetic precursors such as isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are naturally occurring metabolites in mycobacteria and several other microbial pathogens. The broad specificity in the recognition of these molecules by the T-lymphocyte population expressing a Vgamma9Vdelta2 cell receptor might facilitate their manipulation by designing small potent synthetic agonist ligands. In this paper, we describe the synthesis and the biological evaluation of new pyrophosphonate compounds as new isosteric analogues of natural prenyl pyrophosphates. Several prenyl and alkenyl pyrophosphonate with different chain lengths and degrees of insaturation (24-28, 48-50, and 64-66) were tested as well as the alkoxymethylpyrophosphonic analogue of IPP (compound 76) as its closest isostere. Several of them appeared to be better activators of Vgamma9Vdelta2 T cell proliferation than IPP. These results open the perspective of a potential use of isoprenoides pyrophosphonates as specific immunoregulatory molecules.
Subject(s)
Antigens/chemistry , Lymphocyte Activation/drug effects , Organophosphorus Compounds/chemical synthesis , Organophosphorus Compounds/pharmacology , T-Lymphocyte Subsets/drug effects , Antigens/pharmacology , Cell Division/drug effects , Drug Design , Hemiterpenes , Humans , Ligands , Organophosphorus Compounds/immunology , Receptors, Antigen, T-Cell, gamma-delta/analysis , Structure-Activity RelationshipABSTRACT
A new phenolic acid trimer was detected by coupled liquid chromatography/mass spectroscopy in alkali extracts of maize bran. The trimer was purified by preparative silica gel chromatography. The structure of the new compound was elucidated on the basis of 1D and 2D NMR and corresponded to a 4-O-8', 5'-5" dehydrotriferulic acid.
