2. Academic Validation
  3. Identification of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamate-nitrostyrene hybrid as potent antiproliferative and apoptotic inducing agent against cervical cancer cell lines

Identification of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamate-nitrostyrene hybrid as potent antiproliferative and apoptotic inducing agent against cervical cancer cell lines

  • Eur J Med Chem. 2018 Feb 25:146:621-635. doi: 10.1016/j.ejmech.2018.01.020.
Sujay Laskar 1,  Luis Sánchez-Sánchez 2,  Sebastián M Flores 3,  Hugo López-Muñoz 4,  María L Escobar-Sánchez 5,  Manuel López-Ortiz 3,  Marcos Hernández-Rodríguez 6,  Ignacio Regla 7
Affiliations

Affiliations

  • 1 Lab. de Síntesis de Fármacos, Laboratorio 9 UMIEZ, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ejercito de Oriente, Iztapalapa 09230, Ciudad de México, Mexico. Electronic address: sl.sujay@gmail.com.
  • 2 Lab. Biología Molecular del Cáncer, Laboratorio 2 PB UMIEZ, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ejercito de Oriente, Iztapalapa 09230, Ciudad de México, Mexico. Electronic address: luisss@unam.mx.
  • 3 Lab. de Síntesis de Fármacos, Laboratorio 9 UMIEZ, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ejercito de Oriente, Iztapalapa 09230, Ciudad de México, Mexico.
  • 4 Lab. Biología Molecular del Cáncer, Laboratorio 2 PB UMIEZ, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ejercito de Oriente, Iztapalapa 09230, Ciudad de México, Mexico.
  • 5 Lab. Microscopía Electrónica, Depto. Biología Celular, Facultad de Ciencias, Cd. Universitaria, Universidad Nacional Autónoma de México, Coyoacán, 04510, Ciudad de México, Mexico.
  • 6 Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, 04510, Ciudad de México, Mexico.
  • 7 Lab. de Síntesis de Fármacos, Laboratorio 9 UMIEZ, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ejercito de Oriente, Iztapalapa 09230, Ciudad de México, Mexico. Electronic address: regla@unam.mx.
PMID: 29407986 DOI: 10.1016/j.ejmech.2018.01.020
Abstract

The present study seeks to describe the design and synthesis of six new Michael adducts of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamate with nitrostyrenes and their in vitro antiproliferative activity against human cervical Cancer cell lines [HeLa (HPV 18 positive), CaSki (HPV 16 positive) and ViBo (HPV negative) cervical Cancer cell lines]. Virtual screening of the physicochemical properties of all compounds have also been presented. All the compounds exploited significant antiproliferative activity on the three cervical Cancer cell lines. Compound 8a was found to be most potent, displaying in vitro antiproliferative activity against HeLa, CaSki and ViBo cervical Cancer cell lines superior to Cisplatin and Paclitaxel with IC50 values 0.99 ± 0.007, 2.36 ± 0.016 and 0.73 ± 0.002 μM respectively. In addition, compound 8a did not trigger the necrosis cell death to the test Cancer cell lines. Further mechanistic study revealed that compound 8a could inhibit the Cancer cell proliferation by inducing Apoptosis through Caspase-3 activation. Moreover, cell cycle analysis indicated that compound 8a could arrest the cell cycle at the G1 phase for HeLa and CaSki Cancer cells. At the predetermined IC50 values on Cancer cells, compound 8a did not induce any necrotic (cytotoxic) death to the normal human lymphocytes. In the present design, (1S,4S)-2,5-diazabicyclo[2.2.1]heptane system was found to be superior than the piperazine counterpart 11.

Keywords

Antiproliferative; Dithiocarbamate; Necrosis; Nitrostyrene; Pro-apoptotic.

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