Molecular Modeling and In Vitro Evaluation of Piplartine Analogs against Oral Squamous Cell Carcinoma

Abstract

Cancer is a principal cause of death in the world, and providing a better quality of life and reducing mortality through effective pharmacological treatment remains a challenge. Among malignant tumor types, squamous cell carcinoma-esophageal cancer (EC) is usually located in the mouth, with approximately 90% located mainly on the tongue and floor of the mouth. Piplartine is an alkamide found in certain species of the genus Piper and presents many pharmacological properties including antitumor activity. In the present study, the cytotoxic potential of a collection of piplartine analogs against human oral SCC9 carcinoma cells was evaluated. The analogs were prepared via Fischer esterification reactions, alkyl and aryl halide esterification, and a coupling reaction with PyBOP using the natural compound 3,4,5-trimethoxybenzoic acid as a starting material. The products were structurally characterized using 1H and 13C nuclear magnetic resonance, infrared spectroscopy, and high-resolution mass spectrometry for the unpublished compounds. The compound 4-methoxy-benzyl 3,4,5-trimethoxybenzoate (9) presented an IC50 of 46.21 µM, high selectively (SI > 16), and caused apoptosis in SCC9 cancer cells. The molecular modeling study suggested a multi-target mechanism of action for the antitumor activity of compound 9 with CRM1 as the main target receptor.

Piplartine Synthetic Analogs: In Silico Analysis and Antiparasitic Study against Trypanosoma cruzi

“…Products were obtained via four reaction approaches, as shown in Scheme 1: Fisher's esterification (a); esterification using alkyl or aryl halides (b); the Mitsunobu reaction (c); and coupling reactions using PyBOP (benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate) (d) [11].…”

“…For the compound 4-methylbenzyl 3,4,5-trimethoxybenzoate (11), the following 1 H NMR signals were obtained, referring to the aromatic substituent: a doublet to two protons at δ 7.34 (d, J = 8.0 Hz, H-3′, H-5′), another doublet to two hydrogens at δ 7.20…”

“…For the compound 4-methylbenzyl 3,4,5-trimethoxybenzoate (11), the following 1 H NMR signals were obtained, referring to the aromatic substituent: a doublet to two protons at δ 7.34 (d, J = 8.0 Hz, H-3 , H-5 ), another doublet to two hydrogens at δ 7.20 (d, J = 8.4 Hz, H-2 , H-6 ), a singlet to two protons at δ 5.32 (H-7 ), and another singlet at δ 2.36 (s, 3H, H-8 ) referring to methyl hydrogens in the para position of the aromatic ring, and a singlet signal at δ 7.32 ppm (H-2, H-6). In the 13 C NMR, a signal at 138.1 (C-4 ), another signal at 133.1 (C-1 ), a signal to two carbons at 129.2 (C-3 , C-5 ), another signal to two carbons at 128.4 (C-2 , C-6 ), a signal at 66.7 (C-7 ), and a signal at 21.3 referring to methyl in the The trypanocidal effects of compounds 15-18 and 20 against Trypanosoma cruzi (trypomastigote and epimastigote forms) are shown in Table 1.…”

“…In drug candidate research, piplartine (Figure 1) has become increasingly relevant, as it is a natural substance found in the Piperaceae family (a kind of pepper). In the literature, there are already several studies where analogs of piplartine are synthesized and evaluated for different pharmacological activities, namely: antiparasitic, antitumor, and antimicrobial actions [10][11][12]. Of the antiparasitic activities, the most frequent studies are against Trypanosoma and Leishmania [10,13].…”

A Novel MDM2-Binding Chalcone Induces Apoptosis of Oral Squamous Cell Carcinoma

“…The DNA content was analyzed by collecting 10,000 events using a FACScalibur flow cytometer. The data were analyzed using CellQuest (BD Biosciences, Franklin Lakes, NJ, USA) and FlowJo (Tree Star Inc., Ashland, OR, USA) software as in [ 34 ].…”