Polar 3-alkylidene-5-pivaloyloxymethyl-5'-hydroxymethyl-gamma-lactones as protein kinase C ligands and antitumor agents

Abstract

A series of DAG-lactones with polar 3-alkylidene substituents have been investigated as PKC-alpha ligands and antitumor agents. Extensive analysis of structure-activity relationships for the 3-alkylidene chain revealed that polar groups such as ether, hydroxyl, aldehyde, ester, acyloxy, and amido were tolerated with similar binding affinities and reduced lipophilicities compared to the corresponding unsubstituted alkylidene chain. Among the derivatives, compounds 5, 6 and 8 with an ether type of side chain showed high binding affinities in range of K(i)= 3-5 nM and excellent antitumor profiles, particularly against the colo205 colon cancer and the K562 leukemia cell lines.

Figure 1

Scheme 1. Syntheses of Hydroxyl and Ether Analogues

Reagents and Conditions: Reagents and Conditions: (a) CAN, CH₃CN-H₂O, 0 °C; (c) (CH₃)₃CCOCl, Et₃N, DMAP, CH₂Cl₂; (c) LiHMDS, CH₃(CH₂)₁₂CHO for 1–2, RO(CH₂)_nCHO for 3–13, TrO(CH₂)_nCHO for 14–17, THF, −78 °C; (d) MsCl, NEt₃, CH₂Cl₂, DBU; (e) BCl₃, CH₂Cl₂, −78 °C; (f) CF₃CO₂H, CH₂Cl₂, O°C

Scheme 2. Syntheses of Aldehyde and Carboxylate Analogues

Reagents and Conditions: (a) PCC, 4Å MS, CH₂Cl₂; (b) PDC, DMF; (c) TMS-diazomethane, MeOH; (d) C₈H₁₇MgBr, ether, −10 °C; (e) BCl₃, CH₂Cl₂, −78 °C;

Scheme 3. Syntheses of O-Acylated and Amino Analogues

Reagents and Conditions: (a) HCO₂H, CH₂Cl₂, rt; (b) K₂CO₃, MeOH, rt; (c) Ac₂O, NEt₃, DMAP, CH₂Cl₂, rt; (d) (CH₃)₃CCOCl, NEt₃, CH₂Cl₂, rt; (e) CF₃CO₂H, CH₂Cl₂, O°C; (f) PPh₃, DEAD, DPPA, THF, rt; (g) PPh₃, H₂O, THF, rt; (h) BCl₃, CH₂Cl₂, −78 °C