Are you Qingzhi Gao?

Claim your profile

Publications (4)12.22 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The Vitamin D(3) lactone analogues, (23S)- and (23R)-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone (TEI-9647 and TEI-9648) are antagonists of the 1alpha,25-dihydroxyvitamin D(3) (1alpha,25-(OH)(2)D(3)) nuclear receptor (VDR)-mediated differentiation of human leukemia (HL-60) cells. In order to clarify the structure-Vitamin D antagonistic activity relationship, we paid attention to the unique lactone moiety of TEI-9647 and TEI-9648: alpha-exo-methylene-gamma-lactone structure. We synthesized the exo-methylene-modified analogues (methylene saturated, endo-methylene, methylene-deleted, methyl-substituted, dimethyl-substituted, methylene-replaced with dimethyl and cyclopropane) and oxygen-modified analogues (oxygen atom replaced with nitrogen and carbon atom) by convergent method using palladium-catalyzed coupling reaction or direct modification of VD(3) skeleton. The antagonistic activity in HL-60 cell differentiation evaluating system of these analogues revealed that any exo-methylene-modified analogues and nitrogen analogue did not have the antagonistic activity, on the other hand carbon analogue did show. The results suggest that "alpha-exo-methylene carbonyl" structure of VD(3) side-chain is crucial for antagonistic activity. The structure is integral building block of many natural products which have interesting biological and it is thought that Michael-type addition of alpha-exo-methylene carbonyl structure with protein nucleophiles such as cysteine would play an important role for the activities. According to this theory, Michael-type reaction of TEI-9647 and TEI-9648 with cysteine residue in protein related to VDR/VDRE-mediated genomic actions such as VDR would be essential step of the antagonistic action.
    The Journal of Steroid Biochemistry and Molecular Biology 06/2004; 89-90(1-5):31-4. · 3.98 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We examined the effects of two novel 1alpha,25-dihydroxyvitamin D(3)-26,23-lactone (1alpha,25-(OH)(2)D(3)-26,23-lactone) analogs on 1alpha,25(OH)(2)D(3)-induced differentiation of human leukemia HL-60 cells thought to be mediated by the genomic action of 1alpha, 25-dihydroxyvitamin D(3) (1alpha,25-(OH)(2)D(3)) and of acute promyelocytic leukemia NB4 cells thought to be mediated by non-genomic actions of 1alpha,25-(OH)(2)D(3). We found that the 1alpha,25-(OH)(2)D(3)-26,23-lactone analogs, (23S)-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone (TEI-9647) and (23R)-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone (TEI-9648), inhibited differentiation of HL-60 cells induced by 1alpha,25-(OH)(2)D(3). However, 1beta-hydroxyl diastereomers of these analogs, i.e. (23S)-25-dehydro-1beta-hydroxyvitamin D(3)-26, 23-lactone (1beta-TEI-9647) and (23R)-25-dehydro-1beta-hydroxyvitamin D(3)-26,23-lactone (1beta-TEI-9648), did not inhibit differentiation of HL-60 cells caused by 1alpha,25-(OH)(2)D(3). A separate study showed that the nuclear vitamin D receptor (VDR) binding affinities of the 1-hydroxyl diastereomers were about 200 and 90 times weaker than that of 1alpha-hydroxyl diastereomers, respectively. Moreover, none of these lactone analogs inhibited NB4 cell differentiation induced by 1alpha,25-(OH)(2)D(3). In contrast, 1beta,25-dihydroxyvitamin D(3) (1beta,25-(OH)(2)D(3)) and 1beta,24R-dihydroxyvitamin D(3) (1beta,24R-(OH)(2)D(3)) inhibited NB4 cell differentiation but not HL-60 cell differentiation. Collectively, the results suggested that 1-hydroxyl lactone analogs, i.e. TEI-9647 and TEI-9648, are antagonists of 1alpha,25-(OH)(2)D(3), specifically for the nuclear VDR-mediated genomic actions, but not for non-genomic actions.
    FEBS Letters 11/1999; 460(2):297-302. · 3.58 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We examined the effects of two novel 1alpha,25-dihydroxyvitamin D3-26,23-lactone (1alpha,25-lactone) analogues on human promyelocytic leukemia cell (HL-60) differentiation using the evaluation system of the vitamin D nuclear receptor (VDR)/vitamin D-responsive element (DRE)-mediated genomic action stimulated by 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) and its analogues. We found that the 1alpha,25-lactone analogues (23S)-25-dehydro-1alpha-hydroxyvitamin-D3-26,23-lactone (TEI-9647), and (23R)-25-dehydro-1alpha-hydroxyvitamin-D3-26,23-lactone (TEI-9648) bound much more strongly to the VDR than the natural (23S, 25R)-1alpha,25(OH)2D3-26,23-lactone, but did not induce cell differentiation even at high concentrations (10(-6) M). Intriguingly, the differentiation of HL-60 cells induced by 1alpha,25(OH)2D3 was inhibited by either TEI-9647 or TEI-9648 but not by the natural lactone. In contrast, retinoic acid or 12-O-tetradecanoylphorbol-13-acetate-induced HL-60 cell differentiation was not blocked by TEI-9647 or TEI-9648. In separate studies, TEI-9647 (10(-7) M) was found to be an effective antagonist of both 1alpha,25(OH)2D3 (10(-8) M) mediated induction of p21(WAF1, CIP1) in HL-60 cells and activation of the luciferase reporter assay in COS-7 cells transfected with cDNA containing the DRE of the rat 25(OH)D3-24-hydroxylase gene and cDNA of the human VDR. Collectively the results strongly suggest that our novel 1alpha,25-lactone analogues, TEI-9647 and TEI-9648, are specific antagonists of 1alpha, 25(OH)2D3 action, specifically VDR/DRE-mediated genomic action. As such, they represent the first examples of antagonists, which act on the nuclear VDR.
    Journal of Biological Chemistry 07/1999; 274(23):16392-9. · 4.65 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We examined the effects of two novel 1α,25-dihydroxyvitamin D3-26,23-lactone (1α,25-(OH)2D3-26,23-lactone) analogs on 1α,25(OH)2D3-induced differentiation of human leukemia HL-60 cells thought to be mediated by the genomic action of 1α,25-dihydroxyvitamin D3 (1α,25-(OH)2D3) and of acute promyelocytic leukemia NB4 cells thought to be mediated by non-genomic actions of 1α,25-(OH)2D3. We found that the 1α,25-(OH)2D3-26,23-lactone analogs, (23S)-25-dehydro-1α-hydroxyvitamin D3-26,23-lactone (TEI-9647) and (23R)-25-dehydro-1α-hydroxyvitamin D3-26,23-lactone (TEI-9648), inhibited differentiation of HL-60 cells induced by 1α,25-(OH)2D3. However, 1β-hydroxyl diastereomers of these analogs, i.e. (23S)-25-dehydro-1β-hydroxyvitamin D3-26,23-lactone (1β-TEI-9647) and (23R)-25-dehydro-1β-hydroxyvitamin D3-26,23-lactone (1β-TEI-9648), did not inhibit differentiation of HL-60 cells caused by 1α,25-(OH)2D3. A separate study showed that the nuclear vitamin D receptor (VDR) binding affinities of the 1-hydroxyl diastereomers were about 200 and 90 times weaker than that of 1α-hydroxyl diastereomers, respectively. Moreover, none of these lactone analogs inhibited NB4 cell differentiation induced by 1α,25-(OH)2D3. In contrast, 1β,25-dihydroxyvitamin D3 (1β,25-(OH)2D3) and 1β,24R-dihydroxyvitamin D3 (1β,24R-(OH)2D3) inhibited NB4 cell differentiation but not HL-60 cell differentiation. Collectively, the results suggested that 1-hydroxyl lactone analogs, i.e. TEI-9647 and TEI-9648, are antagonists of 1α,25-(OH)2D3, specifically for the nuclear VDR-mediated genomic actions, but not for non-genomic actions.
    Febs Letters - FEBS LETT. 01/1999; 460(2):297-302.