Clarification of the binding mode of teleocidin and benzolactams to the Cys2 domain of protein kinase Cdelta by synthesis of hydrophobically modified, teleocidin-mimicking benzolactams and computational docking simulation.
Phorbol esters (12-O-tetradecanoylphorbol 13-acetate; TPA) and teleocidins are known to be potent tumor promoters and to activate protein kinase C (PKC) by binding competitively to the enzyme. The relationship between the chemical structures and the activities of these compounds has attracted much attention because of the marked structural dissimilarities. The benzolactam 5, with an eight-membered lactam ring and benzene ring instead of the nine-membered lactam ring and indole ring of teleocidins, reproduces the active ring conformation and biological activities of teleocidins. Herein we describe the synthesis of benzolactams with hydrophobic substituents at various positions. Structure-activity data indicate that the existence of a hydrophobic region between C-2 and C-9 and the steric factor at C-8 play critical roles in the appearance of biological activities. We also computationally simulated the docking of teleocidin and the modified benzolactam molecules to the Cys2 domain structure observed in the crystalline complex of PKCdelta with phorbol 13-acetate. Teleocidin and benzolactams fitted well into the same cavity as phorbol 13-acetate. Of the three functional groups hydrogen-bonding to the protein, two hydrogen-bonded with protein atoms in common with phorbol 13-acetate, but the third one hydrogen-bonded with a different protein atom from that in the case of phorbol 13-acetate. The model explains well the remarkable difference in activity between 5 and its analogue having a bulky substituent at C-8.
Endo
Y
Y
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113, Japan. yendo@mol.f.u-tokyo.ac.jp
Takehana
S
S
Ohno
M
M
Driedger
P E
PE
Stabel
S
S
Mizutani
M Y
MY
Tomioka
N
N
Itai
A
A
Shudo
K
K
D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002273:Carcinogens / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003545:Cysteine / Q000378:metabolism*; D004789:Enzyme Activation; D018922:HL-60 Cells; D006801:Humans; D006860:Hydrogen Bonding; D008235:Lyngbya Toxins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008958:Models, Molecular; D018716:Molecular Mimicry; D009000:Monocytes / Q000187:drug effects; D011485:Protein Binding; D011493:Protein Kinase C / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
C111915:BL-8-C10; C111917:BL-V8-23TM; C111916:BL-VA-210; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002273:Carcinogens; D008235:Lyngbya Toxins; D013764:Tetrahydronaphthalenes; C022176:teleocidins; D011493:Protein Kinase C; D003545:Cysteine