Characterization, Modes of Synthesis, and Pleiotropic Effects of Hypocholesterolemic Compounds – A Review
TL;DR: Major natural sources as well as synthetic and biological routes of synthesis of these compounds are reviewed in a concise manner and various HMG-CoA analogues including statins have been reviewed specifically.
Abstract: Studies on the various cholesterol-lowering agents is one of the important areas in clinical research. Identifica- tion and characterization of potential molecules from various sources have been carried out in the past and their relation- ship with the enzymes which are involved in the cholesterol cascade is gaining interest. In this review, we have high- lighted various inhibitors involved in the cholesterol cascade as well as cholesterol-lowering agents, viz., tocotrienol, flavonoids, phytosterols, phytostanols, statins, DADS, and synthetic compounds. The mechanism of action and characteri- zation of these hypocholesterolemic compounds are discussed in this communication. Major natural sources as well as synthetic and biological routes of synthesis of these compounds are reviewed in a concise manner. Especially, various HMG-CoA analogues including statins have been reviewed specifically. In this respect, researchers have identified 2,3- oxidosqualene cyclase-lanosterol synthase (lanosterol syn- thase, oxidosqualene-lanosterol cyclase, lanosterol synthase, 2,3-oxidosqualene-lanosterol cyclase, human lanosterol syn- thase (EC 5.4.99.7)) having a molecular weight of 83 kDa, catalyzing the highly selective cyclization reaction from the substrate 2,3-oxidosqualene (squalene 2,3-epoxide, squalene 2,3-oxide, (S)-squalene-2,3-epoxide, 2,3-epoxisqualene, oxidosqualene) into lanosterol, as an appropriate step for the inhibition of cholesterol biosynthesis (3). Oxidosqualene cyclase inhibitors (OSCI) arrest the downstream of 2,3- oxidosqualene which helps to stimulate epoxysterols to
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TL;DR: In this article, the authors investigated the possible mechanisms for the use of phenolic extracts from grapefruit peels in the management/prevention of cardiovascular complications and found that the phenolic contents of the extracts were investigated using HPLC-DAD.
39 citations
TL;DR: The phenolic compounds and volatile compounds which have been linked with the biological activities of the peels have been characterized and the bioactive compounds of citrus peels and the mechanisms for the biological Activities are looked at.
Abstract: Citrus peels, which are an environmental menace in many developing countries have been in use in folk medicine for the management of some degenerative conditions, though there was limited information on the mechanism of such medicinal properties. These medicinal properties also promote the peels as functional foods; since they are generally regarded as safe and are consumed in some countries in forms of candies, wines, infusions and additives. Studies on the mechanisms for the antioxidant, anti-diabetic, cardioprotective, neuroprotective and anticancer activities of the peels have established the intereaction with some key enzymes relevant to the management of such diseases. The phenolic compounds and volatile compounds which have been linked with the biological activities of the peels have been characterized. This review looks at the bioactive compounds of citrus peels and the mechanisms for the biological activities of the peels.
23 citations
Cites background from "Characterization, Modes of Synthesi..."
...The inhibition of HMG-CoA reductase by phenolic compounds is both competitive with HMG-CoA and non-competitive with NADPH (Sung et al. 2004a, b; Seenivasan et al. 2011)....
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TL;DR: In this article, the authors characterized the soluble free and bound phenolic compounds from shaddock peels and investigated their effect on 3-hydroxy-methyl-3-glutaryl coenzyme A reductase (HMG-CoA) and glutathione-linked enzymes in colon (Caco-2) cells.
10 citations
TL;DR: The estimation of Lovastatin produced by Monascus purpureus and pure lovastatin was attempted by UV-visible spectrophotometer as well as HPLC, and HPLC analysis consistently gave reliable results for the estimation of lovastsatin under all the experimental conditions studied.
Abstract: Development of a novel method for the quantification of lovastatin is an interesting problem in the analytical field. In the literature, many reports use spectrophotometric method for the quantification of lovastatin. However, the analysis of fermentation broth containing lovastatin appears to be inaccurate using spectrophotometric method. Hence, the estimation of lovastatin produced by Monascus purpureus and pure lovastatin was attempted by UV-visible spectrophotometer as well as HPLC. It was observed that the analogues and/or intermediates of lovastatin synthesized in the fermentation broth and the products of fermentation caused superimposition effect on the absorption spectrum. Phosphate is a medium constituent for the production of lovastatin by the organism which contributed significantly to the superimposition of absorption spectrum. On the other hand, HPLC analysis consistently gave reliable results for the estimation of lovastatin under all the experimental conditions studied.
10 citations
TL;DR: Predicted specific substrate utilization and product excretion rates have been correlated well with the experimental observations, which validate the proposed metabolic pathway developed from metabolic footprinting data.
8 citations
References
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TL;DR: Isoflavones identified as inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A in soybean paste were assayed using the catalytic portion of Syrian hamster HMG-CoA reductase, and the kinetic values were measured using HMG -CoA and NADPH.
Abstract: Isoflavones identified as inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in soybean paste were assayed using the catalytic portion of Syrian hamster HMG-CoA reductase, and the kinetic values were measured using HMG-CoA and NADPH. The inhibition of HMG-CoA reductase by these inhibitors was competitive with HMG-CoA and noncompetitive with NADPH. K i values for genistein, daidzein, and glycitein were 27.7, 49.5, and 94.7 μM, respectively.
49 citations
"Characterization, Modes of Synthesi..." refers background in this paper
...Also, these compounds were efficacious in the treatment of cardiovascular disease (CVD), Alzheimer’s disease, renal disease, cancer, bone fracture, allergic encephalomyelitis, multiple sclerosis, immune-mediated neurological disorders, and also diabetes [15, 27, 32, 35, 39, 62, 66-69]....
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...They are genistein, glycitein, and aglycone (Table 1) [34, 35]....
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TL;DR: The x-ray structure of the class II Pseudomonas mevalonii HMG-CoA reductase in complex with the statin drug lovastatin shows a similar mode of binding but marked differences in specific interactions that account for the observed differences in affinity, which might be exploited to develop selective class II inhibitors for use as antibacterial agents against pathogenic microorganisms.
47 citations
"Characterization, Modes of Synthesi..." refers background in this paper
...[13] reported the crystal structure of a lovastatin bound to both class I (human) and class II (bacterial) HMG-CoA reductases....
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...It also displaced the flap domain of the enzyme which contained the catalytic residue His-381 [13, 40, 41, 52]....
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TL;DR: Although the activity of mutant enzymes Glu52----Gln and Asp183----Ala was undetectable under standard assay conditions, their Km values for substrates were 4-300-fold higher than those for wild-type enzyme, and the acidic residue functional in catalysis is judged to be the acidic catalytic residue.
46 citations
TL;DR: A series of novel 4-thiophenyl quinoline-based mevalonolactone derivatives were synthesized from ethyl 6,7,8-trisubstituted-4-chloro-quinoline-3-carboxylates by several reactions and evaluated for their ability to inhibit the rat HMG CoA reductase in vitro.
44 citations
"Characterization, Modes of Synthesi..." refers background in this paper
...Compounds like hydroxyl phosphinyl trans-tetrahydro compactin [20], tocotrienol (a vitamin E analogue) [21], 4-thiophenyl quinoline-based mevalonolactones [22], , -difluoroketones [23], and daidzein (isoflavone) [24] are some of the HMGCoA reductase inhibitors....
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TL;DR: In this paper, a 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitors, more commonly known as statins, represent the gold standard in treating hypercholesterolemia.
Abstract: 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitors, more commonly known as statins, represent the gold standard in treating hypercholesterolemia. Although statins are regarded as generally safe, they are known to cause myopathy and, in rare cases, rhabdomyolysis. Statin-dependent effects on plasma lipids are mediated through the inhibition of HMGR in the hepatocyte, whereas evidence suggests that myotoxicity is due to inhibition of HMGR within the myocyte. Thus, an inhibitor with increased selectivity for hepatocytes could potentially result in an improved therapeutic window. Implementation of a strategy that focused on in vitro potency, compound polarity, cell selectivity, and oral absorption, followed by extensive efficacy and safety modeling in guinea pig and rat, resulted in the identification of compound 1b (BMS-644950). Using this discovery pathway, we compared 1b to other marketed statins to demonstrate its outstanding efficacy and safety profile. With the potential to generate an excellent therapeutic window, 1b was advanced into clinical development.
41 citations
"Characterization, Modes of Synthesi..." refers background in this paper
...Evidence suggests that myotoxicity is due to inhibition of HMG-CoA reductase within the myocyte [19]....
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