Author: novelconjugates

Natural Skin Whitening Agents!

Skin whitening products are commercially available for cosmetic purposes in order to obtain a lighter skin appearance. They are also utilized for clinical treatment of pigmentary disorders such as melasma or postinflammatory hyperpigmentation. Whitening agents act at various levels of melanin production in the skin. Many of them are known as competitive inhibitors of tyrosinase, the key enzyme in melanogenesis. Others inhibit the maturation of this enzyme or the transport of pigment granules (melanosomes) from melanocytes to surrounding keratinocytes. In this review we present an overview of (natural) whitening products that may decrease skin pigmentation by their interference with the pigmentary processes.

In the skin, melanocytes are situated on the basal layer which separates dermis and epidermis. One melanocyte is surrounded by approximately 36 keratinocytes. Together, they form the so-called epidermal melanin unit. The melanin produced and stored inside the melanocyte in the melanosomal compartment is transported via dendrites to the overlaying keratinocytes. The melanin pigment is a polymer produced inside the melanosomes and synthesised from the amino acid l-tyrosine that is converted by the enzyme tyrosinase to dopaquinone. This reaction continues spontaneously via dopachrome to the monomeric indolic precursors (5,6-dihydroxyindole and 5,6-dihydroxyindole 2-carboxylic acid) of the black-brown pigment eumelanin. However, some other enzymes, like the tyrosinase related proteins (TRP-1 and dopachrome tautomerase (TRP-2) may also play an important role in melanogenesis in vivo. Upon reaction with cysteine, dopaquinone forms 2- or 5-S-cysteinyldopa that generates the benzothiazine precursors of the red/yellow pheomelanin polymer. In general, a mixed type of pheo- and eumelanin polymer is produced and deposited onto the melanosomal matrix proteins. Considering the many colour variations that can be seen in the skin and hair, one may expect that the composition of the mixed melanins is regulated in many different ways. However, altered production of cutaneous melanin may cause considerable problems of esthetic nature, especially in hyperpigmentary conditions, like melasma, postinflammatory hyperpigmentation, freckles or lentigines. But also depigmenting conditions, like vitiligo, have high impact on the quality of life of the patients. (Int J Mol Sci. 2009 Dec; 10(12): 5326–5349.)

New natural amino acid-bearing pro-drugs

The biomedical effects of the natural phenol pterostilbene are of great interest but its bioavailability is negatively affected by the phenolic group in position 4′ which is an ideal target for the conjugative enzymes of phase II metabolism. We report the synthesis and characterization of prodrugs in which the hydroxyl moiety is reversibly protected as a carbamate ester linked to the N-terminus of a natural amino acid. Prodrugs comprising amino acids with hydrophobic side chains were readily absorbed after intragastric administration to rats. The Area Under the Curve for pterostilbene in blood was optimal when prodrugs with isoleucine or β-alanine were used. The prodrug incorporating isoleucine was used for further studies to map distribution into major organs. When compared to pterostilbene itself, administration of the isoleucine prodrug afforded increased absorption, reduced metabolism and higher concentrations of pterostilbene, sustained for several hours, in most of the organs examined. Experiments using Caco-2 cells as an in vitro model for human intestinal absorption suggest that the prodrug could have promising absorption profiles also in humans; its uptake is partly due to passive diffusion, and partly mediated by H+-dependent transporters expressed on the apical membrane of enterocytes, such as PepT1 and OATP.