6IQ5

Crystal Structure of CYP1B1 and Inhibitor Having Azide Group

Summary for 6IQ5

• Entry DOI: 10.2210/pdb6iq5/pdb
• Descriptor: Cytochrome P450 1B1, PROTOPORPHYRIN IX CONTAINING FE, 2-(cis-4-azidocyclohexyl)-4H-naphtho[1,2-b]pyran-4-one, ... (4 entities in total)
• Functional Keywords: cytochrome p450, inhibitor, cyp1b1, azide, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 106085.57

Authors

Kubo, M.,Yamamoto, K.,Itoh, T. (deposition date: 2018-11-06, release date: 2019-01-30, Last modification date: 2024-03-27)

Primary citation

Kubo, M.,Yamamoto, K.,Itoh, T.
Design and synthesis of selective CYP1B1 inhibitor via dearomatization of alpha-naphthoflavone.
Bioorg. Med. Chem., 27:285-304, 2019

PubMed Abstract: Selective cytochrome P450 (CYP) 1B1 inhibition has potential as an anticancer strategy that is unrepresented in the current clinical arena. For development of a selective inhibitor, we focused on the complexity caused by sp-hybridized carbons and synthesized a series of benzo[h]chromone derivatives linked to a non-aromatic B-ring using α-naphthoflavone (ANF) as the lead compound. Ring structure comparison suggested compound 37 as a suitable cyclohexyl-core with improved solubility. Structural evolution of 37 produced the azide-containing cis-49a, which had good properties in three important respects: (1) selectivity for CYP1B1 over CYP1A1 and CYP1A2 (120-times and 150-times, respectively), (2) greater inhibitory potency of >2 times that of ANF, and (3) improved solubility. The corresponding aromatic B-ring compound 59a showed low selectivity and poor solubility. To elucidate the binding mode, we performed X-ray crystal structure analysis, which revealed the interaction mode and explained the subtype selectivity of cis-49a.

PubMed: 30553624
DOI: 10.1016/j.bmc.2018.11.045

Experimental method

X-RAY DIFFRACTION (3.7 Å)