Flora Sundersingh

University of Wisconsin–Madison, Madison, Wisconsin, United States

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Publications (3)15.09 Total impact

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    ABSTRACT: As a potential target for obesity, human BCATm was screened against more than 14 billion DNA encoded compounds of distinct scaffolds followed by off-DNA synthesis and activity confirmation. As a consequence, several series of BCATm inhibitors were discovered. One representative compound (R)-3-((1-(5-bromothiophene-2-carbonyl)pyrrolidin-3-yl)oxy)-N-methyl-2'-(methylsulfonamido)-[1,1'-biphenyl]-4-carboxamide (15e) from a novel compound library synthesized via on-DNA Suzuki-Miyaura cross-coupling showed BCATm inhibitory activity with IC50 = 2.0 μM. A protein crystal structure of 15e revealed that it binds to BCATm within the catalytic site adjacent to the PLP cofactor. The identification of this novel inhibitor series plus the establishment of a BCATm protein structure provided a good starting point for future structure-based discovery of BCATm inhibitors.
    ACS Medicinal Chemistry Letters 08/2015; 6(8):919-24. DOI:10.1021/acsmedchemlett.5b00179 · 3.12 Impact Factor
  • Flora Sundersingh · Lori A Plum · Hector F DeLuca ·
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    ABSTRACT: Essential hypertension is a polygenic disorder with a complex and multifactorial nature. Although no single gene is responsible, multiple genes provide incremental contributions to this disorder. Vitamin D is a primary regulator of calcium homeostasis. Epidemiological and clinical studies appear to point to a role for vitamin D in hypertension but direct experimental evidence is lacking. Sprague-Dawley rats were made vitamin D deficient by feeding a purified vitamin D-deficient diet and eliminating all sources of ultraviolet light. Vitamin D deficiency was confirmed by very low serum calcium levels. Blood pressure was measured in conscious rats non-invasively with a volume pressure recording system. Vitamin D deficiency results in elevated blood pressures independent of serum calcium concentration. The administration of 1α,25-dihydroxyvitamin D3 (1,25-(OH)2D3) and a less calcemic analog, 2-methylene-19-nor-20(S)-1α-hydroxyl-bishomopregnacalciferol (2MbisP) significantly reduced blood pressure in these rats. Thus, vitamin D status is one of the determining factors regulating blood pressure. Copyright © 2015. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 04/2015; 461(4). DOI:10.1016/j.bbrc.2015.04.069 · 2.30 Impact Factor
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    ABSTRACT: The requirement for TRPV6 for vitamin D-dependent intestinal calcium absorption in vivo has been examined by using vitamin D-deficient TRPV6 null mice and littermate wild-type mice. Each of the vitamin D-deficient animals received each day for 4 days 50 ng of 1,25-dihydroyvitamin D(3) in 0.1 ml of 95% propylene glycol:5% ethanol vehicle or vehicle only. Both the wild-type and TRPV6 null mice responded equally well to 1,25-dihydroxyvitamin D(3) in increasing intestinal calcium absorption. These results, along with our microarray data, demonstrate that TRPV6 is not required for vitamin D-induced intestinal calcium absorption and may not carry out a significant role in this process. These and previous results using calbindin D9k null mutant mice illustrate that molecular events in the intestinal calcium absorption process in response to the active form of vitamin D remain to be defined.
    Proceedings of the National Academy of Sciences 01/2009; 105(50):19655-9. DOI:10.1073/pnas.0810761105 · 9.67 Impact Factor