Biomedical subjects
Publications and source records attributed to A Ganesan.
[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.
[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.
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.
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.
[reaction: see text] Room-temperature ionic liquids promote various transition metal-catalyzed reactions in the solution phase. Here, for the first time, we show that these effects are translatable to solid-phase reactions. The Suzuki-Miyaura cross-coupling of 4-iodophenol immobilized on polystyrene-Wang resin with various arylboronic acids was significantly accelerated by the ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF(4)(-)]).
1,5-Cyclooctadiene was lithiated under LICKOR superbase conditions followed by reaction with alkyl halides or ethylene oxide to yield 3-substituted 1,5-cyclooctadienes in high yield and purity. This procedure is suitable for preparation of 1,5-cyclooctadienes carrying pendant functional groups for immobilization on solid-phase resins.
Zinc triflate was found to be an effective reagent for the C3-alkylation of indoles by alkyl halides in the presence of Hünig's base and tetrabutylammonium iodide. This new method for indole alkylation proceeds by a S(N)1-like pathway, and is general for allylic, benzylic, and tertiary halides.
The level of sophistication of combinatorial synthesis continues to increase at a heady pace. Fairly complex target molecules are now being assembled combinatorially using a broad palette of organic reactions both in solution- and solid-phase. This review highlights academic and industrial examples of combinatorial synthesis published within the last year. Recent advances in small-molecule synthesis are outlined, ranging from simple acyclic scaffolds to complex natural products.
PURPOSE: Congenital adrenal hyperplasia is the most common cause of androgen mediated virilization of the genitourinary tract in females. In our study relative lengths of the internal genital duct structure were compared with the degree of virilization of the external genitalia. MATERIALS AND METHODS: The records of 9 consecutive female patients with a median age of 2.6 years with congenital adrenal hyperplasia were studied. There were 4 normal females with a median age of 7.4 months who had a voiding cystourethrogram for urinary tract infection used as controls. The patients with congenital adrenal hyperplasia were stratified into groups as having mild, moderate or severe virilization based on preoperative photographs of external genitalia. By lateral voiding cystourethrograms the length of the proximal urethra, vagina and urogenital sinus was measured and standardized against the femoral metaphysis. The relative length of these internal genital structures was compared to the degree of virilization of the external genitalia. RESULTS: There were 4 cases classified as normal, and 2 mildly, 4 moderately and 3 severely virilized. The urogenital sinus appeared to lengthen, with increasing virilization of the external genitalia. There was no trend for the proximal urethra to shorten with increasing virilization. The vagina also seemed to shorten with increasing virilization. CONCLUSIONS: Our results suggest that the vagina enters the urogenital sinus at a fixed distance from the bladder neck. With increasing virilization, the majority of urethral lengthening occurs primarily distal to the vaginal opening, that is urogenital sinus lengthening.
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Subperiosteal orbital abscess (SPA) is a serious complication of paranasal sinusitis, which can lead to blindness or even death. A quick response is necessary as this condition is treatable. Early surgical intervention is indicated if there is risk of visual loss, or if no improvement is observed within 48 hours of starting medical therapy. Three patients with orbital SPA secondary to sinusitis treated successfully by Functional Endoscopic Sinus Surgery (FESS) are presented in this case series. The surgical indications were impending visual loss with an abscess and cellulitis impinging on the optic nerve in one child and in the other two patients, a lack of clinical response within 48 hours after starting systemic antibiotic. CT scans, nasal endoscopy, and ophthalmologic examinations are mandatory during the evaluation process. The advantages of FESS in these patients were the avoidance of external ethmoidectomy and its external facial scar, an early drainage of the affected sinuses, SPA, and the eradication of the disease from the fronto-ethmoidal region leading to an enhanced recovery and a reduced hospital stay. FESS is also a safe, convenient and minimally invasive procedure in patients presenting with serious complications of sinusitis.
The prenylated natural products spirotryprostatin A and B derived from the Trp-Pro diketopiperazine also feature an oxidative rearrangement of the indole to form a spirooxindole. Synthetically, formation of the oxindole ring was stereoselectively accomplished by reaction of the appropriate indole precursor with N-bromosuccinimide. For optimum results, the oxidation should be carried out prior to diketopiperazine cyclization. In this manner, we have synthesized the tetrahydro- and dihydro- analogues of spirotryprostatin B in four steps from L-tryptophan methyl ester. The dihydro derivative was then converted to spirotryprostatin B by unsaturation of the pyrrolidine ring to a pyrroline, thus unambiguously confirming the structure of the natural product.
Tryprostatin B and demethoxyfumitremorgin C are fungal inhibitors of mammalian cell cycle progression at the G(2)/M transition. N-Alkyl derivatives of the L-Trp-L-Pro diketopiperazine were prepared as analogues of tryprostatin B, and two of these were more active than the natural product. A second series of cis- and trans-tetrahydro-beta-carbolines annulated to a diketopiperazine were prepared as analogues of demethoxyfumitremorgin C. The nature of the alkyl substituent, as well as its cis or trans relationship in the tetrahydro-beta-carboline ring, was found to have a significant effect on cytotoxic activity. Small cis-alkyl substituents fall into the demethoxyfumitremorgin C family, whereas bulky benzyl trans compounds appear to act via a different mechanism of action.
Biomimetic total syntheses of glyantrypine, fumiquinazoline F, fumiquinazoline G, and fiscalin B were achieved in four steps from tryptophan methyl ester. In the key step, the anthranilamide residue in a linear tripeptide is dehydrated to a benzoxazine by reaction with triphenylphosphine, iodine, and a tertiary amine. The benzoxazines subsequently undergo rearrangement to the natural products via an amidine intermediate. This dehydrative oxazine to quinazoline route is applicable to a broad range of N-acylanthranilamides, including sterically hindered cases.
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BACKGROUND: The principal agent in the etiology of cervical cancer, i.e., human papillomavirus (HPV) type 16, encodes three oncoproteins, E5, E6, and E7. Structural and mutational studies have identified two potential zinc-finger domains as critical for E6 protein function. We investigated several assays to identify and characterize compounds that interfere with the binding of zinc to E6. METHODS: Thirty-six compounds were selected on the basis of their structure, which would facilitate their participation in sulfhydryl residue-specific redox reactions, and were tested for their ability to release zinc from E6 protein. The zinc-ejecting compounds were then tested for their ability to inhibit E6 binding to E6-associated protein (E6AP) and E6-binding protein (E6BP), two coactivators of E6-mediated cellular transformation. The binding of E6 to E6BP and E6AP was measured by use of surface plasmon resonance (a technique that monitors molecular interactions by measuring changes in refractive index) and by use of in vitro translation assays. The compounds were also tested for their effects on the viability of HPV-containing cell lines. RESULTS: Nine of the 36 tested compounds ejected zinc from E6. Two of the nine compounds inhibited the interaction of E6 with E6AP and E6BP, and one of these two, 4, 4'-dithiodimorpholine, selectively inhibited cell viability and induced higher levels of p53 protein (associated with the induction of apoptosis [programmed cell death]) in tumorigenic HPV-containing cells. CONCLUSION: We have described assay systems to identify compounds, such as 4,4'-dithiodimorpholine, that can potentially interfere with the biology and pathology of HPV. These assay systems may be useful in the development of drugs against cervical cancer, genital warts, and asymptomatic infections by genital HPVs.
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A library of 108 alpha,alpha-difluoromethylenephosphonic acids was prepared by Ugi four-component condensation using Rink-NH2 resin, 4-[(diethoxyphosphinyl) difluoromethyl]benzoic acid, and a set of 18 aldehydes and 6 isonitriles. Following resin cleavage, the diethylphosphonate esters were hydrolyzed with trimethylsilyl bromide to yield the free acids which were assayed for inhibition of PTP alpha, PTP beta and PTP epsilon.