SUPPORTING INFORMATION OPTIMIZING THE MACROCYCLIC DITERPENIC CORE TOWARDS THE REVERSAL OF MULTIDRUG RESISTANCE IN CANCER Rafael Baptista¥, Ricardo J. Ferreira¥*, Daniel J.V.A. dos Santos§*, Miguel X. Fernandes‡, Maria-José U. Ferreira¥ ¥
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av.
Prof. Gama Pinto, 1649-003 Lisboa, Portugal §
REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto,
Rua do Campo Alegre, 4169-007 Porto, Portugal ‡
Instituto Universitario de Tecnologías Biomédicas (ITB), Universidad de La Laguna, 38200, La
Laguna, España * To whom correspondence should be addressed. Tel: +351 217946477; Fax: +351 217946470; E-mail:
[email protected];
[email protected] . This PDF file includes: Figures S1-S2. Figures S3-S4. Figures S5-S6. Figures S7-S8.
Random tree models for MDR1-transfected mouse lymphoma (L5176Y) and human colon adenocarcinoma (Colo320) cells (minimal model). Random tree models for MDR1-transfected mouse lymphoma (L5176Y) and human colon adenocarcinoma (Colo320) cells (full model). Plots of experimental vs. predicted activity values for the training and test sets at the concentration of 2µM, according the 3D-QSAR approach, for the L5176Y and Colo320 cells (MM_ELE model). Plots of experimental vs. predicted activity values for the training and test sets at the concentration of 2µM, according the 3D-QSAR approach, for the L5176Y and Colo320 cells (QM_DEN model).
MDR1-transfected L5176Y cells – Random Tree (3 levels)
BEHv4 < 3.74
≥ 3.74
G2p < 0.17
Mor26p ≥ 0.17
< 0.16
BEHv4 < 3.35
1.7 (6/3.59) Molecules 2 3 4 5 18 21
≥ 3.35
4.2 (5/15.0) Molecules 16 19 20 24 25
≥ 0.16
SPH
Mor26p
G2p
< 0.59 ≥ 0.59
< 0.14 ≥ 0.14
< 0.16 ≥ 0.16
14.2 (2/66.2) Molecules 13 15
1.2 (1/0)
Molecules 1
64.7 (3/17.2) Molecules 6 8 22
86.4 (1/0) Molecules 9
30.6 (6/145)
46.9 (2/184) Molecules 10 17
Molecules 7 11 12 14 23 26
Figure S1. Random tree model for MDR1-transfected mouse lymphoma (L5176Y) cell line (minimal model).
Human COLO320 cells – Random Tree (3 levels)
Mor05p < -7.39
≥ -7.39
vsurf_EDmin3 < -2.77
vsurf_EDmin3
≥ -2.77
< -2.44
GATS4m
Mor26u
< 1.03 ≥ 1.03
< 0.27 ≥ 0.27
8.25 (1/0) Molecules 23
9.85 (1/0) Molecules 22
8.47 (2/0) Molecules 6 15
4.75 (7/4.7) Molecules 8 9 10 11 12 17 25
≥ -2.44
2.85 (2/0.01) Molecules 24 26
G3e < 1.16 ≥ 1.16
1.40 (5/0.05) Molecules 3 13 14 18 19
1.11 (8/0.01) Molecules 1 2 4 5 7 16 20 21
Figure S2. Random tree model for the human colon adenocarcinoma (Colo320) cell line (minimal model).
MDR1-transfected L5176Y cells – Random Tree (Best levels)
BEHv4 < 3.74
≥ -3.74
BEHv4 < 3.71
Mor26p
≥ 3.71
22.4 (1/0)
SPH < 0.53
SPH
Mor26p
Molecule 14
≥ 0.53
SPH
≥ 0.16
< 0.16
< 0.14
BEHv4
Mor26p
< 3.29 ≥ 3.29
< -0.04 ≥ -0.04
≥ 0.14
< 0.63
86.4 (1/0)
BEHv4
Molecule 9
< 3.77 ≥ 3.77
BEHv4
5.85 (1/0) 0.99 (8/0.11) 58.8 (1/0.01) 67.6 (2/0.01) Molecule < 0.52 ≥ 0.52 3
MOR26p < 0.57
Molecules 1 2 4 5 10 20 21 25
11.4 (1/0)
≥ 0.57
Molecule 24
5.66 (2/0.18)
1.71 (1/0)
Molecules 13 16
Molecule 18
Molecule 8
≥ 0.63
Molecule 6 22
< 3.76
8.03 (1/0) ≥ 3.76
BEHv4
< 0.54
Molecule 7
≥ 0.45
60.6 (1/0) 39.0 (2/0.08)
Molecule 10 ≥ 0.54
33.4 (1/0)
22.8 (1/0)
MOR26p < 0.45
< 3.76 ≥ 3.76
SPH
Molecule 12
31.1 (1/0)
Molecules 11 23
Molecule 15
43.4 (1/0)
Molecule 17
Molecule 26
Figure S3. Random tree model for MDR1-transfected mouse lymphoma (L5176Y) cell line (full model).
Human COLO320 cells – Random Tree (Best levels)
Mor05p < -7.39
≥ -7.39
G3e
vsurf_EDmin3 ≥ 0.15
< 0.15
< -2.44
Mor05p < -9.44
Mor26u
≥ -9.44
< 0.27
GATS4m
GATS4m
< 1.12 ≥ 1.12
< 1.16 ≥ 1.16
8.25 (1/0) 8.44 (1/0) 9.1 (1/0) Molecule 23
Molecule 15
Molecule 10
2.85 (2/0.01) Molecule 6
9.85 (1/0) Molecule 22
2.61 (2/0.01)
3.07 (1/0)
Molecules 7 11
Molecule 12
< 0.12
< -5.23
1.10 (2/0) Molecules 2 19
≥ 0.12
4.44 (1/0)
Mor26u
Molecule 17 < 0.35
5.83 (1/0) Molecule 8
≥ -5.23
1.03 (5/0)
Mor05p < -6.40
≥ -2.42
GATS4m
≥ 0.91
Mor05p
Molecules 24 26
vsurf_EDmin3
Mor26u < 0.91
2.85 (2/0.01)
≥ 0.27
< -2.42
≥ -2.44
≥ 0.35
5.59 (1/0) Molecule 9
Molecules 1 4 5 GATS4m 20 21 < 0.88 ≥ 0.88 ≥ -6.40
1.12 (2/0) Molecules 14 16
G3e < 0.17
1.57 (3/0.01) Molecule 3 13 18
≥ 0.17
1.37 (1/0) Molecule 25
Figure S4. Random tree model for the human colon adenocarcinoma (Colo320) cell line (full model).
Figure S5. Plots of experimental vs. predicted activity values for the training and test sets at the concentration of 2 µM, according the 3D-QSAR approach, for the L5176Y cell line (MM_ELE model).
Figure S6. Plots of experimental vs. predicted activity values for the training and test sets at the concentration of 2 µM, according the 3D-QSAR approach, for the Colo320 cell line (MM_ELE model).
Figure S7. Plots of experimental vs. predicted activity values for the training and test sets at the concentration of 2 µM, according the 3D-QSAR approach, for the L5176Y cell line (QM_DEN model).
Figure S8. Plots of experimental vs. predicted activity values for the training and test sets at the concentration of 2 µM, according the 3D-QSAR approach, for the Colo320 cell line (QM_DEN model).
