Recent studies on PKC-natural product interactions, clearly pointed out that PKC recognize ligands because of the presence of selective pharmacophores within the interatomic distance and hydrophobicity associated with the ligand surface. Blumberg and Marquez groups designed a series of conformationally constrained DAG-lactone derivatives as PKC activators, using simpler DAG (4) structure. These compounds are synthetically accessible containing all the required pharmacophores for their interaction with the C1 domain and the constrained structure reduce the entropic penalty caused by flexible DAG (4) upon binding to the C1 domain.36,96,97 The DAG-lactones have stronger binding affinity than DAG, but weaker binding affinity than phorbol esters. To understand the role of hydrophobic group in PKC-C1 domain binding they prepared DAG-lactones with several lipophilic side chains such as the acyl- and alkylidene groups (47-50, Figure 2.3.6).97 They also reported that (2R)- enantiomer of compound 47 specifically interacts with PKCα isoform (Ki value increased up to 1.45 nM).98 The optically pure (2R)-DAG-lactones were prepared within 11 linear steps;
whereas the synthesis of many natural products required more number of reaction steps. DAG γ-lactones have two binding mode such as “sn-1” and “sn-2” mode for the C1 domain (Figure 2.3.6).98,99 The molecular docking analysis of DAG-lactones revealed that, in the “sn- 1” mode the acyl group of lactones was forming hydrogen bond with Gly253 of PKC C1 domain whereas alkylidine functional group was pointing towards the lipid membranes.
Ph.D. Thesis-N. Mamidi. IITG-Chemistry Chapter 1-Introduction
Figure 2.3.6: Structures of synthetic DAG-lactones (47-50). Functional groups that are thought to interact with the C1 domain are highlighted.
The hydroxyl group of DAG-lactones was hydrogen bonded with Thr242 and Leu251of C1 domain same as C20 hydroxyl group of phorbol ester (5). Additionally, in the
“sn-2” mode the carbonyl functional group of lactones ring hydrogen bonded with Gly253 of C1 domain and the alkyl chain of the acyl group was pointed to the lipid membranes whereas the hydroxyl group is hydrogen-bonded to Thr242 and Leu251. However, many DAG- lactones have shown the selective binding with the mixture of PKC isoenzymes.100,101 The compound 49 showed selective binding affinity with a mixture of C1 domain of PKC isoforms.101 However, when the compound 49 interacted with PKCδ the Ki values of the isolated C1a and C1b domain were 2780 and 1.78 nM, respectively. Whereas, compound 49 interacted with the PKCα with Ki values of the C1a and C1b domain were 610 and > 10000 nM, respectively.36
It is also reported that, several DAG-lactones have shown antiproliferative and proapoptotic activity, especially 47 and its pure enantiomer of (2R)-47 exhibited proapoptotic activities in lymph node carcinoma of the prostate (LNCaP) cells.102,103 In addition, the DAG- lactones 47 and 50 have also shown to be active in HIV-1 eradication, in ex vivo culture experiments.104 The structural analysis of these reported C1 domain ligands clearly showed that most of them contain at least one ester group, which is considered one of their major pharmacophores.
2.4. General Methods for the Synthesis of Hydroxyl Group Bearing Esters
Over the years several strategies have been developed for the chemoselective synthesis of esters, which include Lewis acid catalysts,105-111 imidazole carbamates,112 DCC/DMAP reaction,113 triphenylphosphene, iodine conditions such as Mitsunobu reaction and Garegg- Samuelsson reaction.112,114 However, only few methods can be used for the synthesis biological active esters.Some of them we showed below.
Ph.D. Thesis-N. Mamidi. IITG-Chemistry Chapter 1-Introduction
Scheme 2.4.1: Boric Acid Catalyzed Chemoselective Esterification of α-Hydroxycarboxylic Acids
Houston and co-worker reported the chemoselective esterification of α-hydroxyl carboxylic acids in the presence 10-20 mol% of boric acid at mild temperature (scheme 2.4.1). This method successfully converted several α-hydroxycarboxylic acids into their methyl esters in presence of excess of MeOH in good yield, whereas secondary alcohols yields were moderate.105
Scheme 2.4.2: Chemoselective Esterification based on the Mitsunobu reaction
Mitsunobu reaction is one the most effective method in the literature for the selective esterification of carboxylic acids. Appendino and co-workers demonstrated the selective esterification between Phenolic alcohol and phenolic acid under Mitsunobu reaction conditions in 48% of yield (Scheme 2.4.2). This method has shown broad application in the modern organic synthesis.107
Scheme 2.4.3: Chemoselective Esterification based on the Garegg-Samuelsson Reaction
Recently, Rafael Robles and co-workers explored a mild and selective esterification of carboxylic acids based on the Garegg–Samuelsson reaction conditions in the presence of triphenylphosphine, iodine, and imidazole as shown in Scheme 2.4.3.114
Ph.D. Thesis-N. Mamidi. IITG-Chemistry Chapter 1-Introduction
Scheme 2.4.4: Hypervalent Iodine (III) Reagent Iodosodilactone Catalysed Esterification.
In addition, Chi Zhang and co-workers demonstrated using hypervalent iodine reagent iodosodilactone as an efficient regenerated coupling reagent for direct esterification/amidation with triphenylphosphine and 4-dimethylaminopyridine (scheme 2.4.4).This process successfully achieved for the synthesis of macrocyclic lactones, amides, as well as peptides without racemization.115
In a similar approach Selva and co-workers reported chemoselective esterification of hydroxyl group bearing carboxylic acids (62 and 64) using dimethyl carbonate (DMC) and catalytic amount of NaY faujasite at 165°C in good yield (scheme 2.4.5). 116a
Scheme 2.4.5: NaY Catalysed Esterification of Hydroxyl Group Bearing Carboxylic Acids.
Ph.D. Thesis-N. Mamidi. IITG-Chemistry Chapter 1-Introduction Muraleedharan and co-worker reported the chemoselective esterification of carboxylic acids as well as deprotection of Boc/THP/TBDMS groups in the presence of catalytic amount of SmCl3 in a good yield (Scheme 2.4.6).116b Further, Appendino and co-workers described CeCl2 catalyzed chemoselective esterification (Scheme 2.4.6).116c Yamamoto and co-workers established the N-polystyrene-bound 4-boronopyridinium chloride as reusable catalyst for the chemoselective esterification of carboxylic acids (Scheme 2.4.6).116d
Scheme 2.4.6: Lewis Acids Promoted Chemoselective Esterification Methods
In addition, Mashima and co-workers demonstrated the enzyme like tetranuclear zinc cluster [Zn4(OCOCF3)6O] and alkoxy-bridged dinuclear Cobalt complex [Co8(OCOtBu)12O2] promoted chemoselective transesterification methods in the presence of alkyl amines (Scheme 2.4.7).116e,f
Scheme 2.4.7: Zn4(OCOCF3)6O and Co8(OCOtBu)12O2 Promoted Chemoselective Esterification.
Ph.D. Thesis-N. Mamidi. IITG-Chemistry Chapter 1-Introduction