Azumamides A-E: histone deacetylase inhibitory cyclic tetrapeptides from the marine sponge Mycale izuensis.
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Angiogenesis Inhibitors↗
Biomedical subjects
A Ganesan
Publications and source records attributed to A Ganesan.
Secular trends in the prevalence of diabetes and impaired glucose tolerance in urban South India--the Chennai Urban Rural Epidemiology Study (CURES-17).
AIMS/HYPOTHESIS: The aim of this study was to determine the secular trends in prevalence of diabetes and IGT in urban India. MATERIALS AND METHODS: The Chennai Urban Rural Epidemiology Study (CURES) screened 26,001 individuals aged > or =20 years using the American Diabetes Association fasting capillary glucose criteria. The study population, which was representative of Chennai, was recruited by systematic random sampling. Every tenth subject from Phase 1 of CURES was invited to participate in Phase 3 for screening by World Health Organization (WHO) plasma glucose criteria. The response rate was 90.4% (2,350 responders from 2,600 potential subjects). The prevalences of diabetes and IGT in CURES were compared with three earlier studies: two conducted on a representative population of Chennai in 1989 and 1995, and the other the National Urban Diabetes Survey (NUDS) completed in 2000. RESULTS: The overall crude prevalence of diabetes using WHO criteria in CURES was 15.5% (age-standardised 14.3%), while that of IGT was 10.6% (age-standardised 10.2%). Prevalence of diabetes increased by 39.8% (8.3-11.6%) from 1989 to 1995; by 16.3% (11.6-13.5%) between 1995 and 2000; and by 6.0% (13.5-14.3%) between 2000 and 2004. Thus within a span of 14 years, the prevalence of diabetes increased by 72.3% (chi (2) trend 22.23, p < 0.0001). The prevalence of IGT increased by 9.6% from 1989 to 1995 and by 84.6% between 1995 and 2000 (chi 2 trend 52.9, p < 0.0001). However, it decreased by 39.3% between 2000 and 2004 (p < 0.0001). There was a shift in the age at diagnosis of diabetes to a younger age in CURES compared with NUDS. CONCLUSIONS/INTERPRETATION: Compared with earlier studies, the prevalence of diabetes in Chennai, representing urban India, has increased while that of IGT has decreased.
Blood Glucose↗
Solid-phase synthesis in the twenty-first century.
Solid-phase synthesis is a powerful tool for achieving high-throughput chemistry. This review discusses recent diverse examples from my group: the solid-phase synthesis of unsymmetrical guanidines, polymer-supported versions of cyclooctadiene and 9-BBN, a triflate-like linker, the synthesis of tetrahydro-beta-carbolines by the acyliminium Pictet-Spengler reaction, and a total synthesis of the antimycobacterial cyclic depsipeptide natural product kahalalide A.
Alkadienes↗
Solid-phase total synthesis of kahalalide A and related analogues.
The marine natural product kahalalide A, a cyclic depsipeptide, was prepared by total synthesis on solid-phase. A backbone cyclization strategy was followed, using the Kenner sulfonamide safety-catch linker. By NMR comparison of synthetic and naturally isolated material, the stereochemistry of the methylbutyrate side chain was established as (S). Several analogues were synthesized and tested for antimycobacterial activity. The results indicate that the alcohol functional group in the serine and threonine residues is important, while the methylbutyrate side chain can be replaced by an achiral hexanoate with an increase in activity.
Magnetic Resonance Spectroscopy↗
PS-COD and PS-9-BBN: polymer-supported reagents for solution-phase parallel synthesis.
1,5-Cyclooctadiene was deprotonated under LICKOR conditions and reacted with Merrifield resin to afford an immobilized cyclooctadiene in high yield. This polymer is effective as a halogen scavenger, while hydroboration leads to a supported 9-BBN analogue. The latter exhibits similar regioselectivity to 9-BBN in olefin hydroboration. [reaction: see text]
Alkenes↗
The transcriptional coactivator p300 plays a critical role in the hypertrophic and protective pathways induced by phenylephrine in cardiac cells but is specific to the hypertrophic effect of urocortin.
Anacardic acid is an alkylsalicylic acid obtained from cashew-nut-shell liquid, and is a potent inhibitor of p300 histone acetyl-transferase (HAT) activity. We have used anacardic acid to prevent the induction of hypertrophy in isolated neonatal rat cardiomyocytes. Hypertrophy was detected as an increase in cell size, the rearrangement of sarcomeres into a striated pattern, and the induction of embryonic genes beta-MHC and ANF. p300 inhibition was equally effective at preventing hypertrophy whether it was induced by treatment with the alpha1-adrenergic agonist, phenylephrine, or by treatment with urocortin, a member of the corticotrophin-releasing-factor family, which stimulates specific G protein-coupled receptors. Spiruchostatin A is a natural-product inhibitor of histone deacetylases (HDAC) similar to the depsipeptide FK228 molecule. We have recently synthesized spiruchostatin A and now show that, although HDACs act in opposition to HATs, spiruchostatin A has the same effect as anacardic acid, that is, it prevents the induction of hypertrophy in response to phenylephrine or urocortin. Pretreatment with either phenylephrine or urocortin reduced the extent of death observed after the exposure of isolated cardiomyocytes to simulated ischaemia and reoxygenation. Inhibition of p300 or HDAC activity eliminated the protection conferred by phenylephrine; however, it did not affect the protection conferred by urocortin. Therefore, it might eventually be possible to use chemical inhibitors such as these in a therapeutic setting to dissociate the protective effect and hypertrophic effect of urocortin, enhancing the survival of cardiomyocytes exposed to transient ischemia, while inhibiting the hypertrophic pathway that would otherwise be induced concurrently.
Anacardic Acids↗
Novel sulfasalazine analogues with enhanced NF-kB inhibitory and apoptosis promoting activity.
The NF-kB transcription factor plays a key role in the regulation of apoptosis by modulating expression of a wide range of cell death control molecules. NF-kB also plays an important role in human diseases by promoting inappropriate cell survival. Small molecule inhibitors of NF-kB are therefore likely to provide novel therapeutic opportunities. Sulfasalazine (SFZ) is a synthetic anti-inflammatory comprising an aminosalicylate, 5-amino salicylic acid (5-ASA), linked to an antibiotic, sulfapyridine (SPY). SFZ, but not 5-ASA or SPY, inhibits activation of NF-kB. We synthesised a small number of SFZ analogues and determined their ability to inhibit NF-kB activity and promote apoptosis in chronic lymphocytic leukaemia and hepatic stellate cells, where NF-kB plays an important role in cell survival. Remarkably, 3 of the 6 analogues synthesised were significantly more effective (up to 8-fold) inhibitors of NF-kB dependent transcription and this increased activity was associated with enhanced apoptosis. Therefore, it is possible to readily improve the NF-kB inhibiting activity of SFZ and analogues of SFZ may be attractive therapeutic agents for malignancies and chronic liver disease where NF-kB is thought to play a significant role.
Animals↗
Rapid deprotection of N-Boc amines by TFA combined with freebase generation using basic ion-exchange resins.
The deprotection of N-Boc amines was rapidly accomplished using 5 equivalents of TFA in methylene chloride in a focused microwave instrument with irradiation at 60 degrees C for 30 min. The freebase amines are then obtained by scavenging the crude reaction mixture with the basic Amberlyst A-21 ion-exchange resin. This procedure is suitable for the parallel deprotection of N-Boc amines.
Amines↗
A 'triflate-like' tetrafluoroarylsulfonate linker for multifunctional solid-phase organic synthesis.
An arylsulfonate solid-phase linker is suitable for 'traceless' synthesis and Pd(0) catalyzed cross-coupling reactions.
Journal Article↗
Total synthesis of spiruchostatin A, a potent histone deacetylase inhibitor.
The total synthesis of spiruchostatin A was accomplished, unambiguously confirming its structure. Key steps included the use of the Nagao thiazolidinethione auxiliary for a diastereoselective acetate aldol reaction and as an activated acylating agent for amide formation, and macrolactonization by the Yamaguchi protocol. Spiruchostatin A is shown to have biological activity similar to that of FK228, a potent histone deacetylase (HDAC) inhibitor in clinical trials. The spiruchostatin A analogue, epimeric at the beta-hydroxy acid, is inactive, highlighting the importance of stereochemistry at this position for interactions with HDACs.
Enzyme Inhibitors↗
Natural products and combinatorial chemistry: back to the future.
The introduction of high-throughput synthesis and combinatorial chemistry has precipitated a global decline in the screening of natural products by the pharmaceutical industry. Some companies terminated their natural products program, despite the unproven success of the new technologies. This was a premature decision, as natural products have a long history of providing important medicinal agents. Furthermore, they occupy a complementary region of chemical space compared with the typical synthetic compound library. For these reasons, the interest in natural products has been rekindled. Various approaches have evolved that combine the power of natural products and organic chemistry, ranging from the combinatorial total synthesis of analogues to the exploration of natural product scaffolds and the design of completely unnatural molecules that resemble natural products in their molecular characteristics.
Biological Products↗
Natural products as a hunting ground for combinatorial chemistry.
Natural products have a long history of success as biologically active leads for therapeutic agents. The ability to prepare analogues and to discover structure-activity relationships is necessary to truly harness the potential of natural products. Recently, combinatorial chemistry has risen to this challenge, and even fairly complex natural products can be targeted for parallel synthesis. Academic and industrial efforts have employed natural products from the peptide, alkaloid, polyketide, and terpenoid and steroid classes in combinatorial chemistry approaches for the production of medicinally important compounds.
Alkaloids↗
Current strategies to target the anti-apoptotic Bcl-2 protein in cancer cells.
Apoptosis (or programmed cell death) is a genetically controlled "cell suicide" pathway which plays an essential role in deleting excess, unwanted or damaged cells during development and tissue homeostasis. Dysregulation of apoptosis contributes to a wide variety of pathological conditions, including AIDS, cardiovascular disease, infectious disease, autoimmunity and neurodegenerative disorders. Resistance to apoptosis is also a common feature in human malignancies, contributing to both the development of cancer and resistance to conventional therapies such as radiation and cytotoxic drugs, which function by activating apoptotic cell death pathways. Bcl-2 is one of the best characterized cell death control proteins; its overexpression confers resistance to a broad range of apoptosis inducers and the cell survival functions of Bcl-2 are activated by translocation in lymphomas and overexpression in many other cancer types. A wealth of experimental data supports the idea that Bcl-2 is an attractive and tractable target for newer molecularly directed anti-cancer strategies, designed to promote cancer cell death. Here we review current understanding of the mechanism of action and importance of Bcl-2 in cancer cells and progress in developing new agents to target this key survival molecule.
Antineoplastic Agents↗
Total Synthesis of (+)-okaramine J featuring an exceptionally facile N-reverse-prenyl to C-prenyl aza-Claisen rearrangement.
[reaction: see text] The convergent total synthesis of (+)-okaramine J was achieved in a longest linear sequence of 12 steps from l-tryptophan tert-butyl ester. A key reaction was the acid-catalyzed room-temperature aza-Claisen rearrangement of a N-reverse-prenylated hexahydro[2,3-b]pyrroloindole to a C-prenylated derivative.
Journal Article↗
Enzymatic synthesis of an indole diterpene by an oxidosqualene cyclase: mechanistic, biosynthetic, and phylogenetic implications.
Petromindole (1) is an unusual indole diterpene that bears a triterpene-like carbon skeleton, suggesting biogenesis from 3-(omega-oxido-geranylgeranyl)indole (4). We found that lupeol synthase (LUP1) from Arabidopsis thaliana cyclizes 4 to 1. Chiral HPLC comparisons of racemic 1 (from biomimetic cyclization of N-pivaloyl-4) with the LUP1 product and authentic 1 established the absolute stereochemistry of petromindole (3S) as that of cyclic triterpenes. Quantum mechanical calculations and conformational analysis of intermediates in the cyclization of 4 to 1 indicated that petromindole biosynthesis differs fundamentally from that of other indole diterpenes. This analysis revealed that radarins also originate from cyclization of 4 but undergo a backbone rearrangement rather than annulation to indole. The combined results support our hypothesis that native fungal petromindole synthase evolved from a pentacyclic triterpene synthase distant from most other indole diterpene synthases.
Arabidopsis↗
Total synthesis of debromoflustramine B via biomimetic alkylative cyclization.
[reaction: see text] The hexahydropyrrolo[2,3-b]indoline skeleton is readily accessed by the zinc triflate-mediated alkylation of tryptamine derivatives. The methodology was employed in a three-step total synthesis of debromoflustramine B.
Journal Article↗
Highly efficient Lewis acid-catalysed Pictet-Spengler reactions discovered by parallel screening.
High yielding Lewis acid-catalysed one-pot Pictet-Spengler reactions of tryptophan methyl ester and tryptamine with aliphatic and aromatic aldehydes were achieved in short reaction times with the aid of microwave irradiation.
Journal Article↗
Inflammation and angiogenesis in osteoarthritis.
OBJECTIVE: To quantify the relationship between inflammation and angiogenesis in synovial tissue from patients with osteoarthritis (OA). METHODS: Hematoxylin and eosin staining and histologic grading for inflammation were performed for 104 patients who met the American College of Rheumatology criteria for OA and had undergone total joint replacement or arthroscopy. A purposive sample of synovial specimens obtained from 70 patients was used for further analysis. Vascular endothelium, endothelial cell (EC) proliferating nuclei, macrophages, and vascular endothelial growth factor (VEGF) were detected by immunohistochemical analysis. Angiogenesis (EC proliferation, EC fractional area), macrophage fractional area, and VEGF immunoreactivity were measured using computer-assisted image analysis. Double immunofluorescence histochemical analysis was used to determine the cellular localization of VEGF. Radiographic scores for joint space narrowing and osteophyte formation in the knee were also assessed. RESULTS: Synovial tissue samples from 32 (31%) of 104 patients with OA showed severe inflammation; thickened intimal lining and associated lymphoid aggregates were often observed. The EC fractional area, EC proliferation, and VEGF immunoreactivity all increased with increasing histologic inflammation grade and increasing macrophage fractional area. In the synovial intimal lining, VEGF immunoreactivity was localized to macrophages and increased with increasing EC fractional area and angiogenesis. No inflammation or angiogenic indices were significantly correlated with radiographic scores. CONCLUSION: Inflammation and angiogenesis in the synovium are associated with OA. The angiogenic growth factor VEGF generated by the inflamed synovium may promote angiogenesis, thereby contributing to inflammation in OA.
Aged↗