Preparation of 2-Pyridone-Containing Tricyclic Alkaloid Derivatives as Potential Inhibitors of Tumor Cell Proliferation by Regioselective Intramolecular N- and C-Acylation of 2-Pyridone

Abstract

Recently, A-ring alkoxyl subsitituted b-carbolin-1-ones (1, Chart 1) were reported to inhibit colon and lung tumors in a patent literature.1) Subsequently, we found that 3-aryl b-carbolin-1-ones (2) inhibit the proliferation of HeLa cells with IC 50 values in the low micromolar range and that the aromatic substitution on C3 in 2 proved to be essential for their biological activity.2,3) To broaden the scope of previous studies, aryl-substituted 2-pyridone-containing derivatives, such as pyrido[2,1-a]isoindole-4-one (3) and 1H-indeno[1,2-b]pyridine-2-one (4), were designed as our synthetic targets to make it possible to probe their structure-activity relationships.Some alkaloids having frameworks of 3 and 4 occur in nature, 4-7) whose analogues were synthesized more often in laboratories for their potent bioactivities as receptor ligands, [8][9][10] enzyme inhibitors 11) or anti-tumor agents.12,13)Since 3 and 4 are a pair of structural isomers, it is reasonable to expect that they could be prepared from a common precursor, which should have a structure of 6-substituted 2-pyridone allowing a disconnection between methylene and Cring in 3 and 4 (Chart 1). However, neither such precursor nor procedure has been employed for this purpose so far. [14][15][16][17][18][19][20][21][22][23][24][25][26] Since the methods for preparation of 3-unsubstituted 2-pyridone have been well established in recent years, 27-37) herein we report a novel synthetic route to 3 and 4 as shown in Chart 2. The route starts from an aldol condensation between 2-acetylbenzoic acid (5) and aryl aldehyde (6) to yield chalcone (7), which subsequently undergoes a [3ϩ3] annulation to give 2-(2-pyridon-6-yl)benzoic acid (8). Serving as a common precursor, 8 goes through an intramolecular N-acylation to produce 2-aryl pyrido[2,1-a]isoindole-4,6-diones (9), or carries out an intramolecular C-acylation to yield 4-aryl 1-methyl-1H-indeno[1,2-b]pyridine-2,5-diones (11) regioselectively. Results and DiscussionPreparation of 2-Aryl Pyrido[2,1-a]isoindole-4,6-diones (9a-j) Following the known procedure, 38) the mixtures of 2-acetylbenzoic acid (5) and aryl aldehydes 6a-j were treated respectively with NaOH in aqueous EtOH at room temperature for 20 h. As shown in Table 1, the corresponding products 2-(3-aryl acryloyl)benzoic acids (7a-j) were yielded conveniently in high yields. However, the aryl aldehydes bearing an electron-withdrawing group, such as o-, m-, A novel and practical preparation of 2-pyridone-containing tricyclic alkaloid derivatives was developed. By regioselective intramolecular N-and C-acylation of 2-(4-aryl-2-pyridon-6-yl)benzoic acid, a pair of structural isomers 2-aryl pyrido[2,1-a]isoindole-4,6-diones and 4-aryl 1-methyl-1H-indeno[1,2-b]-pyridine-2,5-diones, as potential inhibitors of tumor cell proliferation, were prepared respectively.

A new thermal study of the reaction of 6‐azidopyridones with different amines and hydrazines

“…Reaction of azidopyridones 1 with equimolar amount of o-phenylenediamine (2a), for example, in CHCl 3 for 1 h at room temperature gave the corresponding azidopyridones 3. However, fusion of 1 with 2a,b at 100-110˚C for 10 min., did not give the expected tricycle 5, but rather the previously unknown tricyclic system pyrido [2,3-b]- [1,5]benzodiazepines 4a,b. Alternatively, compound 4a could also be obtained by heating compound 3 at 100-110˚C for 5 min.…”

“…Many pyridine compounds and their derivatives have recently occupied an important place in synthetic organic chemistry due to their pharmacological and therapeutic properities [1][2][3][4][5]. Moreover, 2-pyridones represent an important class of pyridine derivatives.…”

The Discovery of Novel ACA Derivatives as Specific TRPM2 Inhibitors that Reduce Ischemic Injury Both In Vitro and In Vivo

“…41 Compound B2 was prepared through an aldol condensation between 4-pentylbenzaldehyde (16n) and 2-acetylbenzoic acid (19) in ethanol (Scheme 3). 42 Treatment of 4-pentylbenzoic acid (20) with thionyl chloride yielded 4-pentylbenzoyl chloride (21), which then was reacted with 11a in the presence of catalytic amounts of triethylamine to form compound B3 (Scheme 4).…”

“…After it was stirred at rt for another 20 h, the resultant mixture was poured into icy water and neutralized by 1 N HCl. The crude product as a solid was collected by filtration and recrystallized from EtOAc to give compound B2 …”

“…The crude product as a solid was collected by filtration and recrystallized from EtOAc to give compound B2. 42 (E)- The Synthesis of Compound B3. 4-Pentylbenzoic acid 20 (500 mg, 2.6 mmol) and thionyl chloride (3 mL) were heated together under reflux for 4 h. Any unreacted thionyl chloride was removed under reduced pressure, and the crude product 4-pentylbenzoyl chloride 21 was used without further purification.…”