PMID- 31779228
OWN - NLM
STAT- MEDLINE
DCOM- 20200417
LR  - 20200417
IS  - 1420-3049 (Electronic)
IS  - 1420-3049 (Linking)
VI  - 24
IP  - 23
DP  - 2019 Nov 26
TI  - The Masked Polar Group Incorporation (MPGI) Strategy in Drug Design: Effects of 
      Nitrogen Substitutions on Combretastatin and Isocombretastatin Tubulin 
      Inhibitors.
LID - 10.3390/molecules24234319 [doi]
LID - 4319
AB  - Colchicine site ligands suffer from low aqueous solubility due to the highly 
      hydrophobic nature of the binding site. A new strategy for increasing molecular 
      polarity without exposing polar groups-termed masked polar group incorporation 
      (MPGI)-was devised and applied to nitrogenated combretastatin analogues. Bulky 
      ortho substituents to the pyridine nitrogen hinder it from the hydrophobic pocket 
      while increasing molecular polarity. The resulting analogues show improved 
      aqueous solubilities and highly potent antiproliferative activity against several 
      cancer cell lines of different origin. The more potent compounds showed moderate 
      tubulin polymerization inhibitory activity, arrested the cell cycle of treated 
      cells at the G(2)/M phase, and subsequently caused apoptotic cell death 
      represented by the cells gathered at the subG(0)/G(1) population after 48 h of 
      treatment. Annexin V/Propidium Iodide (PI) double-positive cells observed after 
      72 h confirmed the induction of apoptosis. Docking studies suggest binding at the 
      colchicine site of tubulin in a similar way as combretastatin A4, with the polar 
      groups masked by the vicinal substituents. These results validate the proposed 
      strategy for the design of colchicine site ligands and open a new road to 
      increasing the aqueous solubility of ligands binding in apolar environments.
FAU - Gonzalez, Myriam
AU  - Gonzalez M
AD  - Laboratorio de Quimica Organica y Farmaceutica, Departamento de Ciencias 
      Farmaceuticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 
      Salamanca, Spain.
AD  - Instituto de Investigacion Biomedica de Salamanca (IBSAL), Facultad de Farmacia, 
      Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
AD  - Centro de Investigacion de Enfermedades Tropicales de la Universidad de Salamanca 
      (CIETUS). Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de 
      Unamuno, E-37007 Salamanca, Spain.
FAU - Ellahioui, Younes
AU  - Ellahioui Y
AD  - Laboratorio de Quimica Organica y Farmaceutica, Departamento de Ciencias 
      Farmaceuticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 
      Salamanca, Spain.
AD  - Departamento de Biologia y Geologia, Fisica y Quimica Inorganica, ESCET, 
      Universidad Rey Juan Carlos, Calle Tulipan s/n, E-28933. Mostoles, Madrid, Spain.
FAU - Alvarez, Raquel
AU  - Alvarez R
AD  - Laboratorio de Quimica Organica y Farmaceutica, Departamento de Ciencias 
      Farmaceuticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 
      Salamanca, Spain.
AD  - Instituto de Investigacion Biomedica de Salamanca (IBSAL), Facultad de Farmacia, 
      Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
AD  - Centro de Investigacion de Enfermedades Tropicales de la Universidad de Salamanca 
      (CIETUS). Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de 
      Unamuno, E-37007 Salamanca, Spain.
FAU - Gallego-Yerga, Laura
AU  - Gallego-Yerga L
AD  - Laboratorio de Quimica Organica y Farmaceutica, Departamento de Ciencias 
      Farmaceuticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 
      Salamanca, Spain.
AD  - Instituto de Investigacion Biomedica de Salamanca (IBSAL), Facultad de Farmacia, 
      Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
AD  - Centro de Investigacion de Enfermedades Tropicales de la Universidad de Salamanca 
      (CIETUS). Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de 
      Unamuno, E-37007 Salamanca, Spain.
FAU - Caballero, Esther
AU  - Caballero E
AD  - Laboratorio de Quimica Organica y Farmaceutica, Departamento de Ciencias 
      Farmaceuticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 
      Salamanca, Spain.
AD  - Instituto de Investigacion Biomedica de Salamanca (IBSAL), Facultad de Farmacia, 
      Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
AD  - Centro de Investigacion de Enfermedades Tropicales de la Universidad de Salamanca 
      (CIETUS). Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de 
      Unamuno, E-37007 Salamanca, Spain.
FAU - Vicente-Blazquez, Alba
AU  - Vicente-Blazquez A
AD  - Laboratorio de Quimica Organica y Farmaceutica, Departamento de Ciencias 
      Farmaceuticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 
      Salamanca, Spain.
AD  - Instituto de Investigacion Biomedica de Salamanca (IBSAL), Facultad de Farmacia, 
      Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
AD  - Centro de Investigacion de Enfermedades Tropicales de la Universidad de Salamanca 
      (CIETUS). Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de 
      Unamuno, E-37007 Salamanca, Spain.
AD  - Laboratory of Cell Death and Cancer Therapy, Department of Molecular Biomedicine, 
      Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones 
      Cientificas (CSIC), E-28040 Madrid, Spain.
FAU - Ramudo, Laura
AU  - Ramudo L
AD  - Departamento de Fisiologia y Farmacologia, Universidad de Salamanca, Campus 
      Miguel de Unamuno, E-37007 Salamanca, Spain.
FAU - Marin, Miguel
AU  - Marin M
AD  - Laboratorio de Quimica Organica y Farmaceutica, Departamento de Ciencias 
      Farmaceuticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 
      Salamanca, Spain.
AD  - Instituto de Investigacion Biomedica de Salamanca (IBSAL), Facultad de Farmacia, 
      Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
AD  - Centro de Investigacion de Enfermedades Tropicales de la Universidad de Salamanca 
      (CIETUS). Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de 
      Unamuno, E-37007 Salamanca, Spain.
FAU - Sanz, Cristina
AU  - Sanz C
AD  - Laboratorio de Quimica Organica y Farmaceutica, Departamento de Ciencias 
      Farmaceuticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 
      Salamanca, Spain.
AD  - Instituto de Investigacion Biomedica de Salamanca (IBSAL), Facultad de Farmacia, 
      Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
AD  - Centro de Investigacion de Enfermedades Tropicales de la Universidad de Salamanca 
      (CIETUS). Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de 
      Unamuno, E-37007 Salamanca, Spain.
FAU - Medarde, Manuel
AU  - Medarde M
AD  - Laboratorio de Quimica Organica y Farmaceutica, Departamento de Ciencias 
      Farmaceuticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 
      Salamanca, Spain.
AD  - Instituto de Investigacion Biomedica de Salamanca (IBSAL), Facultad de Farmacia, 
      Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
AD  - Centro de Investigacion de Enfermedades Tropicales de la Universidad de Salamanca 
      (CIETUS). Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de 
      Unamuno, E-37007 Salamanca, Spain.
FAU - Pelaez, Rafael
AU  - Pelaez R
AD  - Laboratorio de Quimica Organica y Farmaceutica, Departamento de Ciencias 
      Farmaceuticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 
      Salamanca, Spain.
AD  - Instituto de Investigacion Biomedica de Salamanca (IBSAL), Facultad de Farmacia, 
      Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
AD  - Centro de Investigacion de Enfermedades Tropicales de la Universidad de Salamanca 
      (CIETUS). Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de 
      Unamuno, E-37007 Salamanca, Spain.
LA  - eng
GR  - RTI2018-099474-B-I00/Ministerio de Ciencia, Innovacion y Universidades/
GR  - SA030U16/Consejeria de Educacion, Junta de Castilla y Leon/
GR  - SA262P18/Consejeria de Educacion, Junta de Castilla y Leon/
PT  - Journal Article
DEP - 20191126
PL  - Switzerland
TA  - Molecules
JT  - Molecules (Basel, Switzerland)
JID - 100964009
RN  - 0 (Bibenzyls)
RN  - 0 (Ligands)
RN  - 0 (Pyridines)
RN  - 0 (Tubulin)
RN  - 0 (Tubulin Modulators)
RN  - 7O62J06F18 (combretastatin)
RN  - N762921K75 (Nitrogen)
RN  - NH9L3PP67S (pyridine)
RN  - SML2Y3J35T (Colchicine)
SB  - IM
MH  - Apoptosis/drug effects
MH  - Bibenzyls/*chemistry
MH  - Binding Sites
MH  - Cell Cycle/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Colchicine/chemistry
MH  - Drug Design
MH  - HT29 Cells
MH  - HeLa Cells
MH  - Humans
MH  - Ligands
MH  - MCF-7 Cells
MH  - Molecular Docking Simulation
MH  - Nitrogen/*chemistry
MH  - Pyridines/chemistry
MH  - Solubility/drug effects
MH  - Structure-Activity Relationship
MH  - Tubulin/*metabolism
MH  - Tubulin Modulators/*chemistry
PMC - PMC6930638
OTO - NOTNLM
OT  - colchicine-site
OT  - combretastatins
OT  - cytotoxicity
OT  - docking
OT  - isocombretastatins
OT  - masked polar group introduction
OT  - nitrogenated
OT  - phenstatins
OT  - solubility
OT  - tubulin
COIS- The authors declare no conflicts of interest. The funders had no role in the 
      design of the study; in the collection, analyses, or interpretation of data; in 
      the writing of the manuscript, or in the decision to publish the results.
EDAT- 2019/11/30 06:00
MHDA- 2020/04/18 06:00
PMCR- 2019/11/26
CRDT- 2019/11/30 06:00
PHST- 2019/10/15 00:00 [received]
PHST- 2019/11/18 00:00 [revised]
PHST- 2019/11/21 00:00 [accepted]
PHST- 2019/11/30 06:00 [entrez]
PHST- 2019/11/30 06:00 [pubmed]
PHST- 2020/04/18 06:00 [medline]
PHST- 2019/11/26 00:00 [pmc-release]
AID - molecules24234319 [pii]
AID - molecules-24-04319 [pii]
AID - 10.3390/molecules24234319 [doi]
PST - epublish
SO  - Molecules. 2019 Nov 26;24(23):4319. doi: 10.3390/molecules24234319.