Synthesis of coumaperine derivatives: Their NF-κB inhibitory effect, inhibition of cell migration and their cytotoxic activity.
Coumaperine (an amide alkaloid, present in white piper) and its derivatives were synthesized and investigated for their cytotoxicity against L428 and A549 cells and their NF-κB inhibitory activity. It was found that the coumaperine derivatives CP-9 and CP-38 suppress NF-κB subunits p50 and p65 in nuclear fractions by western blot and by NF-κB luciferase reporter gene assay in a dose dependent manner. Confirmation of these results was obtained by confocal microscopy. CP-9, CP-32 and CP-38 also exhibited dose dependent cell cytotoxicity in a L428 cells expressing constitutively active NF-κB and in A549 cells, with an IC50 value of 43.25 μg/ml, 0.39 μg/ml and 16.85 μg/ml respectively against L428 cells and 57.15 μg/ml, 69.1 μg/ml and 63.2 μg/ml respectively against A549 cells. In addition, the coumaperine derivatives show remarkable inhibitory activity on the cancer cell migration assay against A549 lung adenocarcinoma cells at the concentrations of 5 μg/ml, 10 μg/ml, and 5 μg/ml of CP-9, CP-32 and CP-38 respectively. Aromatic substituents and number of olefinic double bond in coumaperine derivatives found to influence the inhibitory activity. In luciferase reporter gene assay, di-olefin conjugated coumaperine derivatives, CP-38, CP-32 and PIP exhibited higher inhibitory activity than their corresponding tri-olefin conjugated coumaperine derivatives, CP-102, CP-146 and PIP-155 respectively. CP-32 with a stronger electron donating group (-N(CH3)2) showed better inhibitory activity in luciferase reporter gene assay and in cell proliferation of L428 cells. Simple coumaperine derivative (CP-9, with no substituent) effectively inhibited A549 cells proliferation and migration than the other coumaperine derivatives. CP-9 and CP-38 diminish significantly the NF-κB subunits (p50 and p65) of L428 cells in nuclear fractions at the dosage of 10 μg/ml and 30 μg/ml respectively. Which clearly shows that CP-9 and CP-38 inactivate the NF-κB pathway in vitro.
The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, and Oncology Laboratory, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer Sheva, Israel.
Natarajan
N
Nandakumar
Chemistry Division, School of Advanced Sciences, VIT University Chennai Campus, Chennai, Tamilnadu, India.
Subramani
S
Muthuraman
Department of Chemistry, Indian Institute of Technology Madras, Chennai, Tamilnadu, India.
Pushparathinam
P
Gopinath
Chemistry Division, School of Advanced Sciences, VIT University Chennai Campus, Chennai, Tamilnadu, India.
Pattusamy
P
Nithya
The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, and Oncology Laboratory, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer Sheva, Israel.
Jacob
J
Gopas
Chemistry Division, School of Advanced Sciences, VIT University Chennai Campus, Chennai, Tamilnadu, India. Electronic address: sar.org@gmail.com.
Rajendran Saravana
RS
Kumar
D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000276:immunology; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology; D029222:Piper nigrum / Q000737:chemistry; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D016328:NF-kappa B; D010880:Piperidines; C412962:coumaperine
A549 cells; Amide alkaloid; Coumaperine; L428 cells; NF-κB; Piperine