N-acylated sulfonamide sodium salt: a prodrug of choice for the bifunctional 2-hydroxymethyl-4-(5-phenyl-3-trifluoromethyl-pyrazol-1-yl) benzenesulfonamide class of COX-2 inhibitors

Synthesis and biological evaluation of possible prodrugs of COX-2 inhibitors involving sulfonamide and hydroxymethyl groups of 2-hydroxymethyl-4-(5-phenyl-3-trifluoromethyl-pyrazol-1-yl) benzenesulfonamides are described. Out of many options, the sodium salt of N-propionyl sulfonamide demonstrated much improved pharmacological profiles and physicochemical properties suitable for oral as well as parenteral administration.     

Cancer pattern and survival in a rural district in South India

Background: Cancer pattern data are rare and survival data are none from rural districts of India. Methods: The Dindigul Ambilikkai Cancer Registry (DACR) covering rural population of 2 millions in Dindigul district, Tamil Nadu state, South India, registered 4516 incident cancers during 2003–2006 by active case finding from 102 data sources for studying incidence pattern, of which, 1045 incident cancers registered in 2003 were followed up for estimating survival. House visits were undertaken annually for each registered case for data completion. Cancer pattern was described using average annual incidence rates and survival experience was expressed by computing observed survival by actuarial method and age-standardized relative survival (ASRS). Results: The average annual age-standardized rate per 100,000 of all cancers together was higher among women (62.6) than men (51.9) in DACR. The most common cancers among men were stomach (5.6), mouth (4.2) and esophagus (3.7). Cervical cancer (22.1) was ranked at the top among women followed by breast (10.9) and ovary (3.3). DACR incidence rates were lesser by at least two folds and 5-year survival were on par or lower than Chennai metropolitan registry for most cancers. Five-year age-standardized relative survival (%) in DACR was as follows: all cancers (29%), larynx (48), mouth (42), breast/tongue (38) and cervix (37). Conclusion: Cancer incidence was significantly lower, cancer patterns were markedly different and population-based cancer survival was lower in rural areas than urban areas thus providing valuable leads in estimating realistic cancer burden and instituting cancer control programs in India.     

Enhanced Selection of High Affinity DNA-Reactive B Cells Following Cyclophosphamide Treatment in Mice

A major goal for the treatment of patients with systemic lupus erythematosus with cytotoxic therapies is the induction of long-term remission. There is, however, a paucity of information concerning the effects of these therapies on the reconstituting B cell repertoire. Since there is recent evidence suggesting that B cell lymphopenia might attenuate negative selection of autoreactive B cells, we elected to investigate the effects of cyclophosphamide on the selection of the re-emerging B cell repertoire in wild type mice and transgenic mice that express the H chain of an anti-DNA antibody. The reconstituting B cell repertoire in wild type mice contained an increased frequency of DNA-reactive B cells; in heavy chain transgenic mice, the reconstituting repertoire was characterized by an increased frequency of mature, high affinity DNA-reactive B cells and the mice expressed increased levels of serum anti-DNA antibodies. This coincided with a significant increase in serum levels of BAFF. Treatment of transgene-expressing mice with a BAFF blocking agent or with DNase to reduce exposure to autoantigen limited the expansion of high affinity DNA-reactive B cells during B cell reconstitution. These studies suggest that during B cell reconstitution, not only is negative selection of high affinity DNA-reactive B cells impaired by increased BAFF, but also that B cells escaping negative selection are positively selected by autoantigen. There are significant implications for therapy.     

Synthesis and biological activity of novel pyrimidinone containing thiazolidinedione derivatives

A series of pyrimidinone derivatives of thiazolidinediones were synthesized. Their biological activity were evaluated in insulin resistant, hyperglycemic and obese db/db mice. In vitro PPARgamma transactivation assay was performed in HEK 293T cells. PMT13 showed the best biological activity in this series. PMT13 (5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethyl]thiazolidine-2,4-dione) showed better plasma glucose, triglyceride and insulin-lowering activity in db/db mice than rosiglitazone and pioglitazone. PMT13 showed better PPARgamma transactivation than the standard compounds. Pharmacokinetic study in Wistar rats showed good systemic exposure of PMT13. Twenty-eight day oral toxicity study in Wistar rats did not show any treatment-related adverse effects.     

Effect of simulated acid rain on nodulation and nitrogen metabolism in Vigna radiata cultivars

Nodulation was inhibited in plants of green gram (Vigna radiata, cvs. ADT-1 and CO-5) exposed to different levels of simulated acid rain using a mixture of H2SO4, HNO3 and HCl (6:3:1) of pH 2.5, 4.0 and 5.5 in comparison with control (pH 7.0). Protein content of leaves increased in cv. CO-5 but decreased in cv. ADT-1 whereas the nitrate content of leaves increased in cv. ADT-1 but lowered in cv. CO-5. Nitrate reductase activity was increased in the nodular roots of cv. ADT-1 but was decreased in leaves. In cv. CO-5 it was increased in leaves but was insignificantly reduced in the nodules at pH 2.5. The nodule nitrogenase activity increased at pH 4.0 and 2.5 in cv. ADT-1. This revised version was published online in July 2006 with corrections to the Cover Date.     

Deregulated c-myb disrupts interleukin-6- or leukemia inhibitory factor-induced myeloid differentiation prior to c-myc: role in leukemogenesis.

The c-myb proto-oncogene is abundantly expressed in tissues of hematopoietic origin, and changes in endogenous c-myb genes have been implicated in both human and murine hematopoietic tumors. c-myb encodes a DNA-binding protein capable of trans-activating the c-myc promoter. Suppression of both of these proto-oncogenes was shown to occur upon induction of terminal differentiation but not upon induction of growth inhibition in myeloid leukemia cells. Myeloblastic leukemia M1 cells that can be induced for terminal differentiation with the physiological hematopoietic inducers interleukin-6 and leukemia inhibitory factor were genetically manipulated to constitutively express a c-myb transgene. By using immediate-early to late genetic and morphological markers, it was shown that continuous expression of c-myb disrupts the genetic program of myeloid differentiation at a very early stage, which precedes the block previously shown to be exerted by deregulated c-myc, thereby indicating that the c-myb block is not mediated via deregulation of c-myc. Enforced c-myb expression also prevents the loss in leukemogenicity of M1 cells normally induced by interleukin-6 or leukemia inhibitory factor. Any changes which have taken place, including induction of myeloid differentiation primary response genes, eventually are reversed. Also, it was shown that suppression of c-myb, essential for terminal differentiation, is not intrinsic to growth inhibition. Taken together, these findings show that c-myb plays a key regulatory role in myeloid differentiation and substantiate the notion that deregulated expression of c-myb can play an important role in leukemogenicity.     

The mutagenic effects of low level sub-acute inhalation exposure to benzene in CD-1 mice.

Benzene is a widely used chemical and common environmental contaminant. It is carcinogenic in man and animals and is genotoxic in mice, rats, and occupationally exposed humans at doses above one part per million. In order to evaluate the genotoxic effects of prolonged exposures to very low concentrations of benzene, we exposed CD-1 mice to benzene by inhalation for 22 h per day, seven days per week for six weeks at 40, 100 and 1000 parts per billion (ppb). Additional groups were exposed to purified air or were housed in standard plastic cages. The effects of in vivo exposure to benzene were evaluated by using an autoradiographic assay to determine the frequency of mutants which represent mutations at the hypoxanthine-guanine phosphoribosyl transferase (hprt) locus in spleen lymphocytes. At the end of the six weeks exposure period lymphocytes were recovered from the spleens of the mice and cryopreserved prior to assay. Mutant cells were selected on the basis of their ability to incorporate tritiated thymidine in the presence of 6-thioguanine. The weighted mean variant (mutant) frequencies (Vf) of female mice (three per group) were 7.2 x 10(-6) at 0 ppb; 29.2 x 10(-6) at 40 ppb; 62.5 x 10(-6) at 100 ppb and 25.0 x 10(-6) at 1000 ppb. The Vf of unexposed mice housed in standard cages was 13.2 x 10(-6). In male mice the same pattern of response was observed, but the increases in Vf in response to benzene were not as great. In both sexes of mice, the increases at 40 and 100 ppb were significantly greater than at 0 ppb (P less than 0.05). The increase in Vf with exposure to 100 ppb and the decline at 1000 ppb parallel the results observed for chromosome damage in spleen lymphocytes from the same animals (Au et al., Mutation Res., 260 (1991) 219-224). These results indicate that sub-chronic exposure to benzene at levels below the current Occupational Safety and Health Administration Permitted Exposure Limit may induce gene mutations in lymphocytes in mice.     

Polyatomics in zinc isotope ratio analysis of plasma samples by inductively coupled plasma-mass spectrometry and applicability of nonextracted samples for zinc kinetics

Inductively coupled plasma-mass spectrometry (ICP-MS) is a powerful tool for both quantitative multielement analyses of inorganic elements and measurement of isotope ratios (IRs). The main disadvantage of this technique is the existence of polyatomic isobaric interferences at some key masses. Zinc has been investigated for such potential interferences in serum or plasma. The Zn isotopes,⁶⁶Zn and⁶⁸Zn, have no apparent interferences, but³²S¹⁶O₂ and³²S₂ are isobaric with⁶⁴Zn. The possible effects of S and other major components of blood plasma—Na, K, Cl, P, Ca—on Zn IRs were investigated using a series of mineral solutions which simulated human plasma with respect to these elements. The mixture of all mineral elements interfered only with⁶⁴Zn (6.66 ng/mL) and⁷⁰Zn (8.51 ng/mL). Interferences to⁶⁶Zn,⁶⁷Zn, and⁶⁸Zn were minimal containing 0.90, 0.94, and 0.39 ng/mL, respectively. The copresence of Na or S shifted³⁵Cl¹⁶O₂ (atomic mass 67 coming from Cl solution) to³⁵Cl₂ which reduced the contribution to⁶⁷Zn. The hypothesis that Zn IRs obtained from plasma at various intervals after the intravenous administration of enriched⁶⁷Zn to humans would reflect those obtained after extraction of Zn was therefore tested. To compare the two pretreatment methods, “extraction” versus “nonextraction,” specimens were collected from 10 human subjects at intervals of 5 min to 24 h postinjection, and in 4 subjects from 5 min to 9 d postinjection. Two separate aliquots of plasma from each time-point were dried and digested with hydrogen peroxide, and the residue dissolved in nitric acid. One specimen was subjected to zinc extraction using ammonium diethyldithiocarbamate chelate followed by back extraction into nitric acid. The matching aliquot received no further pretreatment. The normalized IRs obtained from⁶⁷Zn/⁶⁶Zn and⁶⁷Zn/⁶⁸Zn in both the “extracted” and “nonextracted” samples agreed well(r ² = 0.976 andr ² = 0.985, respectively) compared to those from other ratios (r ² = 0.838 for⁶⁷Zn/⁶⁴Zn andr ² = 0.747 for⁶⁷Zn/⁷⁰Zn). Considering the minimum possibility of isobaric interferences in plasma samples,⁶⁷Zn/⁶⁸Zn obtained from “nonextracted” samples is sufficient for routine Zn kinetic analysis by ICP-MS.     

Synthesis and structure-activity relationships of andrographolide analogues as novel cytotoxic agents

Andrographolide 1, the cytotoxic agent of the plant Andrographis paniculata was subjected to semi-synthetic studies leading to the preparation of a number of potent and novel analogues. Of the analogues synthesized, while 8,17-epoxy andrographolide 6 retained the cytotoxic activity of 1, ester derivatives of 6 exhibited considerable improvement in activity. Lower activity was observed when the epoxy moiety in the triacetate 9, derived from 6 was modified. Synthesis and structure-activity relationships are discussed.