Antiglycation Studies of Pd(II)-Hydrazide Complexes

Antiglycation Studies of Pd(II)-Hydrazide ComplexesIntroductionGlycation is a non-enzymatic spontaneous answer between moolahs and coexisting protein followed by a complex cascade of reactions including dehydration, redox reaction and early(a) rearrangements 1, 2 forming pass on glycation end products ( geezerhoods) 3. Glycation reactions depend on the propagation of reactive oxygen species by trace amounts of redox active metal ions 4 and on the degree and continuance of hyperglycemia in vivo 5. Glycation damages the collagen and elastin throughout the body. It is generally accepted that accretion of tissue AGEs together with enhanced oxidative stress has an important graphic symbol in the progression of senescence and diabetic complications including retinopathy, neuropathy, embryopathy, delayed healing of wounds and others 6-10. The improver in diabetic complications is the major cause of increased morbidity and deathrate rate that has enhanced considerably in the two decades 11. It has been estimated that the number of cases of DM will reach to 366 million by 2030 12, 13 showing in concomitant a great challenge to healthc ar systems 14. The failure of existing antidiabetic drug drugs ar forcing researchers to find out new keep downors of proteins responsible for glycation in commit to have a long term and sustainable solution for steering of diabetes and age-re latishd diseases.Protein Glycation The protein glycation, as well called Millard reaction, packs non-enzymatic coupling of proteins with simplification sugars ultimately producing advanced end products. The glycation is a spontaneous reaction, which stimulates the degradation of proteins with variety of their structures and biological activity 1-3. Various reduction sugars including glucose, lactose, fructose, xylose, deoxyribose and galactose may take part in protein glycation 15.Chemistry and mechanics of Protein GlycationThe protein glycation process initiates with the react ion of carbonyl (keto or aldehydic) sort out of reducing sugar with forgo amino free constitutional group of protein forming a labile Schiff base 16. This is called proterozoic stage of glycation. The Schiff bases atomic number 18 then transformed through Amadori rearrangement into comparatively unchanging compounds cognize as Amadori products. At vitriolicic pH or on a lower floor oxidative conditions, the Amadori products or Schiff bases undergo degradation generating extremely reactive 1, 2-dicarbonyl compounds, much(prenominal) as methylglyoxal ( insure 94) 17-21. The administration of protein dicarbonyls through a protein enediol may generate superoxide anion melodic themes in the presence of musical passage metal ions and molecular oxygen 22. The superoxide radicals can be converted into most reactive hydroxyl radical via Fenton reaction 7. The reactive carbonyl compounds subsequently react with amino groups of neighboring proteins producing protein dicarbonyl compounds, which further contribute in the formation of various types of protein crosslinks and adducts called Advanced Glycation nullify Products (AGEs). The autoxidation of Amadori products to AGEs is described as glycoxidation process. run into 94. Structures of few reactive dicarbonyl glycation median(a)sAdvanced Glycation end ProductsThe advanced glycation end products (AGEs) comprise a complex heterogeneous group of compounds produced primarily through the reaction of reactive carbonyls and proteins. AGEs demonstrate to have versatile molecular biological functions and structures 18, 23. The amino, sulphydryl and guanidinum functional groups occurring in the intracellular and extracellular proteins are the main targets of reactive carbonyl compounds. Various AGEs have been recognized in different tissues that can be categorized into three major groups fluorescent cross-linked AGEs (e.g. pentosidine and crossline), non-fluorescent cross-linked AGEs (e.g. alkyl formyl gl ycosyl pyrrole and arginine-lysine imidazole cross-links) and non-cross linked AGEs (e.g. pyrraline and N-(carboxylmethyl) lysine) 18. The structures of some AGEs are presented in Figure 95.Figure 95. Structures of selected advanced glycation end productsFactors Affecting the Formation of AGEsIn physiological environment, the generation of AGEs is a relatively slow process. Accordingly, the AGEs accumulation is dominant in long-lived structural proteins, for instance, tissue collagens and lens crystallins. The oxidative conditions are known to accelerate the formation of AGEs, which slows down under anaerobic environment 24. The transition metal ions may induce the auto-oxidation of sugars to produce keto aldehydes and hydrogen peroxide that drive on up the formation of AGEs 25. The amount of AGEs formed is increased as a function of cadence and concentration of glucose and hence the AGEs formation is enhanced with aging and under diabetic conditions 26.Site Specificity of Glycat ion of ProteinsGlycation of protein is considered as a specific reaction however, it is less specific compared to enzymatic glycosylation. Glycation often takes place at alter commit in the protein, much(prenominal) as the substrate binding site (e.g. Arg-39) of RNase, the allosteric site (e.g. V1) of hemoglobin, and the drug binding sites (e.g. Arg-410) on albumin 27. The specificity of glycation may be determined by endogenous ligands and the structure of protein particularly an amino acid sequence within the protein. The specificity of protein glycation is usually affected by both elemental and acidic neighboring groups 28, either via catalysis of Amadori rearrangement (the rate-limiting step of protein glycation), or via effecting pKa of amino group that contributes in enhancing its nucleophilicity and formation kinetics of Schiff bases. This shows that there is a sport in the respective rate and extent of glycation shown by amino groups in the protein. The anionic ligands also catalyze the potential glycation of proteins at specific sites 27. exogenous Sources of AGEsThe formation of AGEs via Maillard reaction was originally described for physical and chemical deepens occurring during thawing of food 29. Beside the natural formation of AGEs inside the body, there are some exogenous sources of increased AGEs including diet enriched with AGEs and smoking. The extent of absorption of AGEs ingested with food is in truth small 30. However, there is a strong relationship of AGEs circulating in the human body with the AGEs ingested 31.It has been investigated that tobacco smoke increases the formation of AGEs on germ plasm proteins due to containing some products, which produce protein crosslinks and AGE-like fluorescence and mutagenicity 32. For example, the diarbonyl compounds, glyoxal and metbylglyoxal, are most likely to be present in cigarette smoke that act as mediators of AGE formation and formed by thermal decomposition of existing saccharides. Accordingly, the serum of diabetic smokers reveals enhanced takes of AGEs relative to diabetic non-smokers 33. Similarly, the smokers are more nonimmune to incidence of cataract, cardiovascular and lungs diseases as compared to non-smokers due to smoke-mediated AGEs formation 34.Toxicity or Pathological Conditions Associated to Glycation and AGEs FormationThe AGEs are more prone to proteolysis and degradation as compared to the original proteins. The accumulation of AGEs has toxic biological make, causing disruption of umteen cellular processes leading to various pathologies. The AGEs as well as intermediate glycation products such as reactive carbonyls induce the production of free radicals in vitro and in vivo 35, 36 and hence increased oxidative stress 37. The glycation-mediated free radicals are the major cause of protein fragmentation as well as oxidation of lipids (lipid peroxidation) and nucleic acids 7.The reactive dicarbonyls have might to bind with naturally active p roteins of diverse physiology via intra- and inter-molecular cross linking resulting in deactivation of enzymes, transcription factors, membrane transporters and auguring components with eventual protein degradation and cyto toxicity 38-40. The AGEs also bind to cell membrane receptors inducing signal cascades leading to inappropriate gene expressions and cellular activities 18.The elevated level of AGEs in tissues has a strong correlation with severity of diabetic complications 41, 42. This is because of modification of enzymatic activity in multiple ways including binding of ligand, change in protein half life, increased membrane permeability, decreased binding ability of insulin to its receptors, increased atherogenicity of LPL and variation in the immunogenicity 43-45. The main diabetic complications include afflicted wound healing and the serious damage and failure of various zippy organs such as kidneys (nephropathy), nerves (neuropathy), eyes (cataract, retinopathy), blood vessels (atherosclerosis) and tenderheartedness (cardiomyopathy) 11, 34, 46, 47. The AGEs formation is also associated to aging, Alzheimers disease and other chronic disorders 17, 10, 48-50. innate(p) Biological Defense Mechanism against Glycation and AGEsThe human body presents a indisputable mechanics to inhibit the glycation of protein and resulting AGEs formation. For example, -keto-glutaraldehyde dehydrogenase, a liver enzyme, has a capability to vacant 3-deoxyglucosone (3-DG), Arnadori-derived reactive intermediate and hence close outs the generation of AGEs 41. The other enzymes such as aldose reductase and glyoxylase system (I and II) can catalyze the deglycation of reactive intermediate methylglyoxal into D-lactase 51. Amadoriases are the group of enzymes found in Aspergillus, which catalyze the deglycation of Amadori products 52. Some NADPH-dependant exogenous enzymes such as aldose reductase and oxoaldehyde reductase that metabolize -dicarbonyls, have the ability to r educe 3-DG and thus regulate the formation of AGEs 53. Similarly, different plasma amines may reduce AGEs formation through reaction with carbonyl groups of sugar and Amadori compounds 54. Antioxidants such as vitamin E and vitamin C, provide vindication against glycation-mediated free radicals, whereas, ceruloplasmin and other transport proteins bind with transition metal ions such as Cu2+, preventing them to take part in glycoxidation reactions or autoxidative glycation 55.Inhibition of Protein Glycation and AGEsseveral(prenominal) attempts have been made earlier to explore pharmacologically active antiglycating agents to prevent or slow down the production of AGEs 56. The major side effect associated with antiglycation therapy limit the use and necessitate the discovery of new inhibitors of glycation with decreased toxicity and long half life to be implicated for large time span. Currently, two therapeutic strategies are highly successful having great forte against diabetic c omplications and normal aging one is the crushing of formation of AGEs and other is the breaking of already open up AGEs cross-linkages 57.Promising Inhibitors of Glycation with Their Mechanism of InhibitionThe antiglycating agents such as aminoguanidine, rutin, antioxidants, aspirin and other AGEs circuit breakers have been examined extensively and standard great interest. The structures of some potential antiglycating agents are depicted in Figure 96.AminoguanidineAminoguanidine is a derivative of hydrazine that inhibits the generation of AGEs and glucose-derived collagen cross-links during in vitro studies 58. Aminoguanidine does not act on already formed AGEs but it reacts with reactive Amadori products such as 3-deoxyglucosone preventing excess rearrangements and intermediates crosslinking 59. In addition, aminoguanidine is a free radical scavenger that contributes in reducing oxidative stress 60. The treatment of diabetic animal models with aminoguanidine reduces AGEs accu mulation, kidney lesions, albuminuria and long-run diabetic complications including retinopathy, nephropathy and neuropathy 61. Aminoguanidine also exerts positive effect on the whet of nerve conduction 22. Aminoguanidine therapy is limited by serious toxic effects attributable to high reactivity, subliminal concentrations and rapid renal clearance. The human trials with aminoguanidine gravel vasculitis (inflammation of lymph or blood vessel), liver function abnormalities 62 and less frequent flu-like symptoms, sickness and headache 63.Figure 96. Structures of some potential antiglycating agentsAspirinAcetylsalicylic acid commonly known as aspirin is an moderating has well known analgesic drug that also shows the preventive action against formation of cataract under diabetic conditions. Aspirin may limit the sugar-mediated formation of Amadori products by acetylation of free amino residues of proteins. Aspirin also stops the crosslinking of tendon in rat potty in vitro throug h inhibition of glycoxidation. Furthermore, aspirin is a free radical scavenger 64. However, the use of aspirin is unlikely in controlling late diabetic complications because of some serious gastrointestinal side effects 41.RutinRutin is a common flavonoid of vegetables and fruits that modulates the AGEs generation in vitro. The flavonoids including rutin that contain vicinal dihydroxyl groups have established their significant role as antiglycating agents. The mechanism of inhibition by rutin is suggested to involve the trapping of amino groups in proteins at early stage of glycation, especially in ketoamine formation, by rutin metabolites like keto-quinone intermediates. Rutin has shown significant inhibitory effect against hemoglobin glycation and it is more efficient compared to aminoguanidine 65.AntioxidnatsSince non-enzymatic glycation of protein is significantly accelerated by excessive generation of free radicals, the antioxidants and other free radical scavengers are expect ed to inhibit the process of glycation 24. For example, vitamin E has been reported to appreciably reduce the glycation of hemoglobin 66. The compounds that endanger both antioxidant and antiglycation properties e.g. aminosalicylic acid, can protect endothelial cells with better efficacy than aminoguanidine against untoward effects of glycation and high glucose levels in vitro 46. Similarly, carnosine that is a naural antioxidant and antiglycating agent, inhibits sugar-induced cross-linking of proteins by reaction with methylglyoxal and also sequesters metal ions (e.g. copper and zinc). Carnosine has shown its role in the treatment of cataracts and other diseases 67. The glycation-derived free radicals generation may be reduced by chelation of transition metal ions, which are responsible for monosaccharide autoxidation. For instance, the metal chelator, diethylenetriamine penta acetic acid has shown the inhibition of glucose autoxidation 68, 69.AGE-BreakersAGE-breakers are the com pounds, which remove AGEs cross-links through breakdown of -dicarbonyl bonds in glucose-derived cross-links of proteins 70. However, the exact mechanism of inhibition for cross-link breaking is unclear so far. N-phenacylthiazolium bromide (PTB) and its chloride form, alagebrium chloride (ALT-711) are the examples of AGE-breakers. It has been demonstrated that the increased arterial stiffness colligate to diabetes is successfully change through a short treatment with AGE-breaker, ALT-711. The cardiovascular stiffness related to normal aging process can also be reduced by ALT-711. For example, the treatment of normal aged dogs with AGE cross-link breaker has shown noticeable decrease in stiffness of left ventricle sleeping accommodation 71.The clinical trial studies on diabetic humans, dogs and other animals indicate the potentially promising use of antiglycation therapy in near future to prevent diabetic complications and other diseases related to protein glycation 56.