26964-29-4Relevant articles and documents
Structure-activity relationship of flavonoids as potent inhibitors of carbonyl reductase 1 (CBR1)
Arai, Yuki,Endo, Satoshi,Miyagi, Namiki,Abe, Naohito,Miura, Takeshi,Nishinaka, Toru,Terada, Tomoyuki,Oyama, Masayoshi,Goda, Hiroaki,El-Kabbani, Ossama,Hara, Akira,Matsunaga, Toshiyuki,Ikari, Akira
, p. 51 - 56 (2015)
Human carbonyl reductase 1 (CBR1), a member of the short-chain dehydrogenase/reductase superfamily, reduces a variety of carbonyl compounds including therapeutic drugs. CBR1 is involved in the reduction of the anthracycline anticancer drugs to their less anticancer C-13 hydroxy metabolites, which are cardiotoxic. CBR1 inhibitors are thought to be promising agents for adjuvant therapy with twofold beneficial effect in prolonging the anticancer efficacy of the anthracyclines while decreasing cardiotoxicity, a side effect of the drugs. In this study, we evaluated 27 flavonoids for their inhibitory activities of CBR1 in order to explore the structure-activity relationship (SAR). Among them, luteolin (2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4H-1-benzopyran-4-one) showed the most potent inhibition (IC5095 nM), which is also more potent compared to all known classes of CBR1 inhibitors. The inhibition of luteolin was noncompetitive with respect to the substrate in the NADPH-dependent reduction direction, but CBR1 exhibited moderate NADP+-dependent dehydrogenase activity for some alicyclic alcohols, in which the luteolin inhibition was competitive with respect to the alcohol substrate (Ki59 nM). The SAR of the flavonoids indicated that the 7-hydroxy group of luteolin was responsible for the potent inhibition of CBR1. The molecular docking of luteolin in CBR1-NADPH complex showed that theflavonoid binds to the substrate-binding cleft, in which its 7-hydroxy group formed a H-bond with main-chain oxygen of Met234, in addition to H-bond interactions (of its 5-hydroxy and 4-carbonyl groups with catalytically important residues Tyr193 and/or Ser139) and a π-stacking interaction (between its phenyl ring and Trp229).
Synthesis and biological activities of flavonoid derivatives as A3 adenosine receptor antagonists
Karton, Yishai,Jiang, Ji-Long,Ji, Xiao-Duo,Melman, Neli,Olah, Mark E.,Stiles, Gary L.,Jacobson, Kenneth A.
, p. 2293 - 2301 (2007/10/03)
A broad screening of phytochemicals has demonstrated that certain flavone and flavonol derivatives have a relatively high affinity at A3 adenosine receptors, with K(i) values of ≥1 μM (Ji et al. J. Med. Chem. 1996, 39, 781-788). We have further modified the flavone structure to achieve a degree of selectivity for cloned human brain A3 receptors, determined in competitive binding assays versus [125I]AB-MECA [N6-(4-amino-3- iodebenzyl)adenosine-5'-(N-methyluronamide)]. Affinity was determined in radioligand binding assays at rat brain A1 and A(2A) receptors using [3H]- N6-PIA ([3H]-(R)-N6-phenylisopropyladenosine) and [3H]CGS21680 [[3H]-2- [[4-(2-carboxyethyl)phenyl]ethylamino]-5'-(N-ethylcarbamoyl)adenosine], respectively. The triethyl and tripropyl ether derivatives of the flavonol galangin, 4, had K(i) values of 0.3-0.4 μM at human A3 receptors. The presence of a 5-hydroxyl group increased selectivity of flavonols for human A3 receptors. The 2',3,4',7-tetraethyl ether derivative of the flavonol morin, 7, displayed a K(i) value of 4.8 μM at human A3 receptors and was inactive at rat A1/A(2A) receptors. 3,6-Dichloro-2'-(isopropyloxy)-4'- methylflavone, 11e, was both potent and highly selective (~200-fold) for human A3 receptors (K(i) = 0.56 μM). Among dihydroflavonol analogues, the 2-styryl instead of the 2-aryl substituent, in 15, afforded selectivity for human A3 vs rat A1 or A(2A) receptors. The 2-styryl-6-propoxy derivative, 20, of the furanochromone visnagin was 30-fold selective for human A3 receptors vs either rat A1 or A(2A) receptors. Several of the more potent derivatives effectively antagonized the effects of an agonist in a functional A3 receptor assay, i.e. inhibition of adenylyl cyclase in CHO cells expressing cloned rat A3 receptors. In conclusion, these series of flavonoids provide leads for the development of novel potent and subtype selective A3 antagonists.
PHOTOSENSITIZED (SET) CONVERSION OF 2'-HYDROXYCHALCONES TO FLAVONOIDS A PROBABLE BIOGENETIC PATHWAY
Pandey, G.,Krishna, A.,Kumaraswamy, G.
, p. 4615 - 4616 (2007/10/02)
2'-Hydroxychalcones undergo transformation to flavonoids by photoinduced single electron transfer processes.
