Organic Carbamates in Drug Design!

Carbamate-bearing molecules play an important role in modern drug discovery and medicinal chemistry. Organic carbamates (or urethanes) are structural elements of many approved therapeutic agents. Structurally, the carbamate functionality is related to amide-ester hybrid features and, in general, displays very good chemical and proteolytic stabilities. Carbamates are widely utilized as a peptide bond surrogate in medicinal chemistry. This is mainly due to their chemical stability and capability to permeate cell membranes. Another unique feature of carbamates is their ability to modulate inter- and intramolecular interactions with the target enzymes or receptors. The carbamate functionality imposes a degree of conformational restriction due to the delocalization of nonbonded electrons on nitrogen into the carboxyl moiety. In addition, the carbamate functionality participates in hydrogen bonding through the carboxyl group and the backbone NH. Therefore, substitution on the O- and N-termini of a carbamate offers opportunities for modulation of biological properties and improvement in stability and pharmacokinetic properties. Carbamates have been manipulated for use in the design of prodrugs as a means of achieving first-pass and systemic hydrolytic stability. Carbamate derivatives are widely represented in agricultural chemicals, such as pesticides, fungicides, and herbicides. They play a major role in the chemical and paint industry as starting materials, intermediates, and solvents. Furthermore, organic carbamates serve a very important role as optimum protecting groups for amines and amino acids in organic synthesis and peptide chemistry.

Peptide-based molecules are an important starting point for drug discovery, especially in the design of enzyme inhibitors. Because of their high affinity and specificity toward biological functions, peptide-based molecules also serve as valuable research tools. However, the poor in vivo stability, inadequate pharmacokinetic properties, and low bioavailability have generally limited their broader utility. Hence, a variety of peptide mimics are being developed to improve drug-like character along with increased potency, target specificity, and longer duration of action. To this end, several classes of peptidomimetics are tailored by replacing the native amide bond with unnatural linkages such as retro-amide, urea, carbamate, and heterocycles as peptide bond surrogates. These functionalities confer metabolic stability toward aminopeptidases, the enzymes involved in the metabolism of peptide-like drugs. The carbamate’s emerging role in medicinal chemistry is also due to its chemical stability and to its capability to increase permeability across cellular membranes. These attributes of organic carbamates have been exploited in drug design. As a result, the carbamate motif is becoming the choice for peptide bond surrogates.

Over the years, a variety of carabamates have been prepared by utilizing the Hofmann rearrangement of amides, the Curtius rearrangement of acyl azides,the reductive carbonylation of nitroaromatics, the carbonylation of amines, the reaction of alcohols with isocyanates, and carbon dioxide alkylation.The Hofmann rearrangement is well-recognized as a useful method to convert primary carboxamides to amines or carbamates, characterized by the reduction of one carbon in the structure.Much effort has been devoted to the development of modified reagents to optimize the Hofmann rearrangement since the classical method for this transformation, involving the use of an alkaline solution of bromine, is unsatisfactory and unreliable. A variety of oxidants and bases have been proposed as modified agents, e.g., iodine(III) reagents such as PhI(OAc)2, MeOBr, NBS-CH3ONa, NBS-KOH, lead tetraacetate, and benzyltrimethylammonium tribromide. These modified methods, however, require more than 1 equiv or an excess amount of the oxidizing reagent, which is not very convenient.The Curtius rearrangement is the thermal decomposition of acyl azides into the isocyanate intermediate. This method is widely employed in the transformation of carboxylic acids into carbamates and ureas. Acyl azides are usually prepared from carboxylic acid derivatives such as acyl chlorides, mixed anhydrides, and hydrazides. Subsequent isocyanate intermediates can be trapped by a variety of nucleophiles to provide the carbamate derivatives. The acid chloride method is not suitable for acid-sensitive functionalities. One-pot transformations of carboxylic acids into carbamates avoids the isolation of unstable acyl azides. However, protocols involving the use of diphenylphosphoryl azide (DPPA) for the one-pot Curtius reaction are also characterized by issues related to toxicity and the high boiling point of DPPA, which creates difficulties during workup and purification. Other general methods for carbamate preparation involve the use of the highly toxic phosgene,61 phosgene derivatives, or isocyanates. (J Med Chem. 2015 Apr 9; 58(7): 2895–2940.)

Amino Acid Carbamates As Prodrugs Of Resveratrol

Resveratrol (3, 5, 4′-trihydroxy-trans-stilbene), a plant polyphenol, has important drug-like properties, but its pharmacological exploitation in vivo is hindered by its rapid transformation via phase II conjugative metabolism. One approach to bypass this problem relies on prodrugs. We report here the synthesis, characterization, stability and in vivo pharmacokinetic behaviour of prodrugs of resveratrol in which the OH groups are engaged in an N-monosubstituted carbamate ester (-OC(O)NHR) linkage with a natural amino acid (Leu, Ile, Phe, Thr) to prevent conjugation and modulate the physicochemical properties of the molecule. We also report a convenient, high-yield protocol to obtain derivatives of this type. The new carbamate ester derivatives are stable at pH 1, while they undergo slow hydrolysis at physiological pH and hydrolyse with kinetics suitable for use in prodrugs in whole blood. After administration to rats by oral gavage the isoleucine-containing prodrug was significantly absorbed, and was present in the bloodstream as non-metabolized unaltered or partially deprotected species, demonstrating effective shielding from first-pass metabolism. We conclude that prodrugs based on the N-monosubstituted carbamate ester bond have the appropriate stability profile for the systemic delivery of phenolic compounds.

All compounds turned out to be highly stable at pH values close to that of the human stomach, no reaction occurring over 24 hours at 37 °C in 0.1 N HCl, and they underwent slow hydrolysis at near-neutral pH (pH 6.8, representing intestinal pH) thus ensuring protection of the phenolic moieties from first pass metabolism during absorption in the gastrointestinal tract. In contrast all the synthesized prodrugs hydrolyzed in murine whole blood, with kinetics suitable for use as prodrugs. (Sci Rep. 2015 Oct 14;5:15216. )

Synthesis of amino acid conjugates of tetrahydrocurcumin

Tetrahydrocurcumin (THC), the hydrogenated and stable form of curcumin, exhibits physiological and pharmacological activities similar to curcumin. A protocol has been developed for the synthesis of novel conjugates of THC with alanine (2a), isoleucine (2b), proline (2c), valine (2d), phenylalanine (2e), glycine (2f) and leucine (2g) in high yields (43–82%). All the derivatives of THC exhibited more potent anti-microbial activity than THC against Bacillus cereus, Staphylococcus aureus, Escherichia coli and Yersinia enterocolitica. The MIC values of the derivatives were 24–37% of those for THC in case of both Gram-positive and Gram-negative bacteria. Derivatives 2g and 2d exhibited maximum anti-mutagenicity against Salmonella typhimurium TA 98 and TA 1538, respectively at a low concentration of 313 μg/plate, with comparable activity for THC evident only at 3750 μg/plate. These results clearly demonstrated that the conjugation of THC at the phenolic position with amino acids led to significant improvement of its in vitro biological attributes.(Food Chem. 2013 Aug 15;139(1-4):332-8.)

Phytocompound-based nanocosmeceuticals!

Phytocompounds have been used in cosmeceuticals for decades and have shown potential for beauty applications, including sunscreen, moisturizing and antiaging, and skin-based therapy. The major concerns in the usage of phyto-based cosmeceuticals are lower penetration and high compound instability of various cosmetic products for sustained and enhanced compound delivery to the beauty-based skin therapy. To overcome these disadvantages, nanosized delivery technologies are currently in use for sustained and enhanced delivery of phyto-derived bioactive compounds in cosmeceutical sectors and products. Nanosizing of phytocompounds enhances the aseptic feel in various cosmeceutical products with sustained delivery and enhanced skin protecting activities. Solid lipid nanoparticles, transfersomes, ethosomes, nanostructured lipid carriers, fullerenes, and carbon nanotubes are some of the emerging nanotechnologies currently in use for their enhanced delivery of phytocompounds in skin care. Aloe vera, curcumin, resveratrol, quercetin, vitamins C and E, genistein, and green tea catechins were successfully nanosized using various delivery technologies and incorporated in various gels, lotions, and creams for skin, lip, and hair care for their sustained effects. However, certain delivery agents such as carbon nanotubes need to be studied for their roles in toxicity. This review broadly focuses on the usage of phytocompounds in various cosmeceutical products, nanodelivery technologies used in the delivery of phytocompounds to various cosmeceuticals, and various nanosized phytocompounds used in the development of novel nanocosmeceuticals to enhance skin-based therapy.

Phytobioactive compounds used in cosmeceuticals include catechins, gallic acids, epicatechins, curcumin, hydroxylbenzoic and cinnamic acids, quercetin, ascorbic acids, luteolin, alpha and beta carotene, complex polysaccharides, and fatty acids. These compounds, in addition to their cosmetic effects, enhance antibacterial, antifungal, anticarcinogenic, and anti-inflammatory biological actions. Even though various macrosized phytobioactive compounds are used in cosmeceutical formulations, their solubility and formulation type have limitations in enhancing the effect of phyto-based cosmeceuticals and therapy The major limitations of phyto-based cosmeceutical therapy include less skin penetration, lower prolongevity, less final quality and lower whitening effects. These qualities depend on the solubility and size of the active phytocompounds. This leads us in search of novel, highly promising technologies for enhanced skin health efficiency of cosmeceutical products. (Int J Nanomedicine. 2016; 11: 1987–2007.)

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.