Synthesis, biological evaluation and SAR of 3-benzoates of ingenol for treatment of actinic keratosis and non-melanoma skin cancer

Bioorganic and Medicinal Chemistry Letters

Volumn 24, Issue 1, 2014, Pages 54-60

  Grue Sørensen, Gunnar ^a   Liang, Xifu ^a   Månsson, Kristoffer ^a   Vedsø, Per ^a   Dahl Sørensen, Morten ^a   Soor, Anke ^a   Stahlhut, Martin ^a   Bertelsen, Malene ^a   Engell, Karen Margrethe ^a   Högberg, Thomas ^a  

^a LEO PHARMA A S   (Denmark)

Author keywords

Cell death induction; Cytokine release; Ingenol 3 benzoates; Molecular modeling; Oxidative burst; PKC activation

Indexed keywords

INGENOL MEBUTATE; PROTEIN KINASE; PROTEIN KINASE DELTA; UNCLASSIFIED DRUG; BENZOIC ACID DERIVATIVE; INGENOL; INGENOL 3 BENZOATE DERIVATIVE;

ACTINIC KERATOSIS; ARTICLE; BIOLOGICAL ACTIVITY; DRUG SCREENING; DRUG STABILITY; DRUG STRUCTURE; DRUG SYNTHESIS; NON MELANOMA SKIN CANCER; ADULT; FEMALE; HUMAN; HUMAN CELL; STRUCTURE ACTIVITY RELATION;

CELL DEATH INDUCTION; CYTOKINE RELEASE; INGENOL 3-BENZOATES; MOLECULAR MODELING; OXIDATIVE BURST; PKCΔ ACTIVATION;

ANTINEOPLASTIC AGENTS; BENZOATES; CELL DEATH; CYTOKINES; DITERPENES; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG SCREENING ASSAYS, ANTITUMOR; HUMANS; KERATOSIS, ACTINIC; MODELS, MOLECULAR; MOLECULAR DOCKING SIMULATION; MOLECULAR STRUCTURE; PROTEIN KINASE C-DELTA; PROTEIN KINASE INHIBITORS; SKIN NEOPLASMS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84891495662     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2013.11.073     Document Type: Article

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34. The molecular dynamics (MD) calculations of PKCδ bound to compounds 10 and 9 were performed with MacroModel (OPLS-2005, water, TNCG minimization, 25 ps equilibrium followed by 2 ns simulation, 1.5 fs time step). The ligand and all atoms in residues within 5 Å of the ligand were allowed to move freely, while residues in a second shell of 5 Å were constrained (force constant 200) and the remaining atoms frozen. The docked pose (Fig. 2a) was used as the starting conformation for 10. The starting conformation of the benzylether 9 was obtained by reducing the ester carbonyl to a methylene group. 500 structures were sampled for each simulation.
35. The docking of ingenol-3-benzoate 10 to the 1PTR crystal structure of the PKCδ C1 domain was performed in two steps. First, low-energy conformations (less than 21 kJ/mol) were obtained from a MacroModel conformational search (OPLS-2005, Water, TNCG minimization, Mixed torsional/Low-mode sampling, 1000 conformations). Secondly, the resulting conformations were docked rigidly with Glide XP to PKCδ with no scaling of the protein atoms. Default Glide settings were used for the ligand scaling and maximum 5 poses per conformation were kept. The highest scoring docked pose is shown in Fig. 2a, the MacroModel conformational energy of the ligand is 6.7 kJ/mol.
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41. max indicates the maximal response in relation to 1.
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43. 50 was calculated as the concentration of test compound producing 50% loss of metabolic activity.
44. 50 determinations were performed in duplicate.