IMPACT OF SUBSTITUENTS IN INDOLOBENZAZOCIN-8-ONE DERIVATIVES ON ANTICANCER ACTIVITY: INSIGHTS FROM MOLECULAR DOCKING AND ADMET PREDICTIONS

ARTHORN LOISRUANGSIN; SASIWADEE BOONYA-UDTAYAN; WEENAWAN SOMPHON

doi:10.22159/ajpcr.2025v18i6.53858

Authors

ARTHORN LOISRUANGSIN Department of Physical and Material Sciences, Faculty of Liberal Arts and Science, Kasetsart University (Kamphaeng-Saen Campus), Nakhon Pathom, Thailand https://orcid.org/0000-0001-7796-7074
SASIWADEE BOONYA-UDTAYAN Department of Physical and Material Sciences, Faculty of Liberal Arts and Science, Kasetsart University (Kamphaeng-Saen Campus), Nakhon Pathom, Thailand https://orcid.org/0000-0002-8121-8233
WEENAWAN SOMPHON Department of Physical and Material Sciences, Faculty of Liberal Arts and Science, Kasetsart University (Kamphaeng-Saen Campus), Nakhon Pathom, Thailand.

DOI:

https://doi.org/10.22159/ajpcr.2025v18i6.53858

Keywords:

Molecular docking, pharmacokinetics, indolobenzazocin-8-one, tubulin polymerization

Abstract

Objectives: The objective of the study is to explore how substitutions modulate indolobenzazocin-8-one’s anticancer activity and advantages over taxanes using computational modeling.

Methods: Molecular docking predicted binding affinities (Ei, kcaL/moL) at β-tubulin’s colchicine site, while ADMET models evaluated physicochemical/ pharmacokinetic properties. Spearman’s rank correlation analysis was employed for assessing structural- activity relationships.

Results: Cytotoxicity was primarily driven by cellular permeability, evidenced by a strong negative correlation between lipophilicity and potency (logD7.4-IC₅₀: ρ=−0.90, p=0.037), unlike the weak, non-significant association with binding affinity (Ei-IC₅₀: ρ=0.46, p=0.434). Methoxy substitution weakened binding (ΔEi increased up to 4.2 kcaL/moL) and had non-linear lipophilicity effects (mono-substitution: ΔlogD7.4=+0.031; di-substitution: ΔlogD7.4=−0.128). Hydroxy substitution enhanced affinity (ΔEi=−1.58 kcaL/moL) but compromised permeability (ΔlogD7.4=−0.095). The optimized lead compound balanced these trade-offs, showing high intestinal absorption (Caco-2 permeability (log cm/s)=−5.033) and low P-glycoprotein efflux risk (probability=0.117).

Conclusion: Substitutions affect anticancer activity by altering both hydrophobicity and binding affinity. Unsubstituted indolobenzazocin-8-one demonstrated the most potent anticancer activity. In addition, its drug-like properties and bypass of P-gp-mediated resistance position it as a superior oral alternative to taxanes.

Downloads

Download data is not yet available.

References

Boonya-Udtayan S, Eno M, Ruchirawat S, Mahidol C, Thasana N. Palladium-catalyzed intramolecular C-H amidation: Synthesis and biological activities of indolobenzazocin-8-ones. Tetrahedron. 2012;68(50):10293-10301. doi: 10.1016/j.tet.2012.10.011

Brancale A, Silvestri R. Indole, a core nucleus for potent inhibitors of tubulin polymerization. Med Res Rev. 2007;27(2):209-238. doi: 10.1002/med.20080, PMID 16788980

Colley HE, Muthana M, Danson SJ, Jackson LV, Brett ML, Harrison J, et al. An orally bioavailable, indole-3-glyoxylamide based series of tubulin polymerization inhibitors showing tumor growth inhibition in a mouse xenograft model of head and neck cancer. J Med Chem. 2015;58(23):9309-9333. doi: 10.1021/acs.jmedchem.5b01312, PMID 26580420

Kumbhar BV, Panda D, Kunwar A. Interaction of microtubule depolymerizing agent indanocine with different human αβ tubulin isotypes. PLoS One. 2018;13(3):e0194934. doi: 10.1371/journal. pone.0194934, PMID 29584771

Song J, Guan YF, Liu WB, Song CH, Tian XY, Zhu T, et al. Discovery of novel coumarin-indole derivatives as tubulin polymerization inhibitors with potent anti-gastric cancer activities. Eur J Med Chem. 2022;238:114467. doi: 10.1016/j.ejmech.2022.114467, PMID 35605363

Wittmann C, Dömötör O, Kuznetcova I, Spengler G, Reynisson J, Holder L, et al. Indolo[2,3-e]benzazocines and indolo[2,3-f]benzazonines and their copper(II) complexes as microtubule destabilizing agents. Dalton Trans. 2023;52(29):9964-9982. doi: 10.1039/d3dt01632c, PMID 37431840

Hong Y, Zhu YY, He Q, Gu SX. Indole derivatives as tubulin polymerization inhibitors for the development of promising anticancer agents. Bioorg Med Chem. 2022;55:116597. doi: 10.1016/j. bmc.2021.116597, PMID 34995858

Goel B, Jaiswal S, Jain SK. Indole derivatives targeting colchicine binding site as potential anticancer agents. Arch Pharm (Weinheim). 2023;356(10):e2300210. doi: 10.1002/ardp.202300210, PMID 37480173

Ren Y, Wang Y, Liu J, Liu T, Yuan L, Wu C, et al. X-ray crystal structure-guided discovery of novel indole analogues as colchicine-binding site tubulin inhibitors with immune-potentiating and antitumor effects against melanoma. J Med Chem. 2023;66(10):6697-6714. doi: 10.1021/acs.jmedchem.3c00011, PMID 37145846

Liu X, Jin J, Wu Y, Du B, Zhang L, Lu D, et al. Fluoroindole chalcone analogues targeting the colchicine binding site of tubulin for colorectal oncotherapy. Eur J Med Chem. 2023;257:115540. doi: 10.1016/j. ejmech.2023.115540, PMID 37301075

Hurysz B, Evans BA, Laryea RN, Boyer BE, Coburn TE, Dexter MS, et al. Synthesis, modeling, and biological evaluation of anti-tubulin indole-substituted furanones. Bioorg Med Chem Lett. 2023;90:129347. doi: 10.1016/j.bmcl.2023.129347, PMID 37236376

Li Y, Yang J, Niu L, Hu D, Li H, Chen L, et al. Structural insights into the design of indole derivatives as tubulin polymerization inhibitors. FEBS Lett. 2020;594(1):199-204. doi: 10.1002/1873-3468.13566, PMID 31369682

Xia LY, Zhang YL, Yang R, Wang ZC, Lu YD, Wang BZ, et al. Tubulin inhibitors binding to colchicine-site: A review from 2015 to 2019. Curr Med Chem. 2020;27(40):6787-67814. doi: 10.2174/092986732666619 1003154051, PMID 31580244

Li W, Shuai W, Sun H, Xu F, Bi Y, Xu J, et al. Design, synthesis and biological evaluation of quinoline-indole derivatives as anti-tubulin agents targeting the colchicine binding site. Eur J Med Chem. 2019;163:428-442. doi: 10.1016/j.ejmech.2018.11.070, PMID 30530194

Li W, Sun H, Xu F, Shuai W, Liu J, Xu S, et al. Synthesis, molecular properties prediction and biological evaluation of indole-vinyl sulfone derivatives as novel tubulin polymerization inhibitors targeting the colchicine binding site. Bioorg Chem. 2019;85:49-59. doi: 10.1016/j. bioorg.2018.12.015, PMID 30599412

Hanwell MD, Curtis DE, Lonie DC, Vandermeersch T, Zurek E, Hutchison GR. Avogadro: An advanced semantic chemical editor, visualization, and analysis platform. J Cheminform. 2012;4(1):17. doi: 10.1186/1758-2946-4-17, PMID 22889332

Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, et al. UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem. 2004;25(13):1605-1612. doi: 10.1002/jcc.20084, PMID 15264254

Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. Autodock4 and autodocktools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009;30(16):2785-2791. doi: 10.1002/jcc.21256, PMID 19399780

Laskowski RA, Swindells MB. LigPlot+: Multiple ligand-protein interaction diagrams for drug discovery. J Chem Inf Model. 2011;51(10):2778-2786. doi: 10.1021/ci200227u, PMID 21919503

Corporation M, Microsoft. Excel. Microsoft 365, Microsoft 2024.

O’Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open babel: An open chemical toolbox. J Cheminform. 2011;3(1):33. doi: 10.1186/1758-2946-3-33, PMID 21982300

Fu L, Shi S, Yi J, Wang N, He Y, Wu Z, et al. ADMETlab 3.0: An updated comprehensive online ADMET prediction platform enhanced with broader coverage, improved performance, API functionality and decision support. Nucleic Acids Res. 2024;52(W1):W422-W431. doi: 10.1093/nar/gkae236, PMID 38572755

ACD. Version 14.01. Chem, Sketch (Freeware), Toronto, ON, Canada: Advanced Chemistry Development, Inc.; 2015. Available from: https:// www.acdlabs.com

Kotthoff I, Kundrotas PJ, Vakser IA. Dockground scoring benchmarks for protein docking. Proteins. 2022;90(6):1259-1266. doi: 10.1002/ prot.26306, PMID 35072956

Bocianowski J, Wrońska-Pilarek D, KrysztofiakKaniewska A, Matusiak K, Wiatrowska B. Comparison of Pearson’s and spearman’s correlation coefficients for selected traits of Pinus sylvestris L. Biom Lett. 2024;61(2):115-135.

Eclarin PR, Yan PA, Paliza CL, Ibasan B, Basiloy PR, Gante NA, et al. Benchmarking the distribution coefficient of anticancer lead compounds using the predicted log D values of clinically approved chemotherapeutic drugs. J Prev Diagn Treat Strateg Med. 2022;1(2):143-152. doi: 10.4103/jpdtsm.jpdtsm-31-22

Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem. 2002;45(12):2615-2623. doi: 10.1021/ jm020017n, PMID 12036371

Zavrsnik D, Spirtović S, Muratović S. The 4-arylaminocoumarin derivatives log P values calculated according to Rekker’s method. Bosn J Basic Med Sci. 2003;3(4):37-40. doi: 10.17305/bjbms.2003.3491, PMID 16232136

Keruckas J, Lygaitis R, Simokaitiene J, Grazulevicius JV, Jankauskas V, Sini G. Influence of methoxy groups on the properties of 1,1-bis(4-aminophenyl)cyclohexane based arylamines: Experimental and theoretical approach. J Mater Chem. 2012;22(7):3015-3027. doi: 10.1039/c2jm14387a

Sparano JA, Gray RJ, Ravdin PM, Makower DF, Pritchard KI, Albain KS, et al. Clinical and genomic risk to guide the use of adjuvant therapy for breast cancer. N Engl J Med. 2019;380(25):2395-2405. doi: 10.1056/NEJMoa1904819, PMID 31157962

Dumontet C, Jordan MA. Microtubule-binding agents: A dynamic field of cancer therapeutics. Nat Rev Drug Discov. 2010;9(10):790-803. doi: 10.1038/nrd3253, PMID 20885410

Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly in vitro by Taxol. Nature. 1979;277(5698):665-667. doi: 10.1038/277665a0, PMID 423966

Škubník J, Pavlíčková V, Ruml T, Rimpelová S. Current perspectives on taxanes: Focus on their bioactivity, delivery and combination therapy. Plants (Basel). 2021;10(3):569. doi: 10.3390/plants10030569, PMID 33802861

Lei L, Wang XJ, Tang SC. Novel taxanes in development: Hopes or hypes? Crit Rev Oncol Hematol. 2022;176:103727. doi: 10.1016/j. critrevonc.2022.103727, PMID 35644326

Jabir RS, Naidu R, Annuar MA, Ho GF, Munisamy M, Stanslas J. Pharmacogenetics of taxanes: Impact of gene polymorphisms of drug transporters on pharmacokinetics and toxicity. Pharmacogenomics. 2012;13(16):1979-1988. doi: 10.2217/pgs.12.165, PMID 23215890

Brooks TA, Kennedy DR, Gruol DJ, Ojima I, Baer MR, Bernacki RJ. Structure-activity analysis of taxane-based broad-spectrum multidrug

resistance modulators. Anticancer Res. 2004;24(2A):409-415. PMID 15152938

Wang Y, Feng F, Chen L, Zhao H, Tian L. Isolation, identification and characterization of potential impurities in cabazitaxel and their formation. Magn Reson Chem. 2014;52(12):783-788. doi: 10.1002/ mrc.4125, PMID 25123687

Tian Y, Lei Y, Wang Y, Lai J, Wang J, Xia F. Mechanism of multidrug resistance to chemotherapy mediated by P-glycoprotein (Review). Int J Oncol. 2023;63(5):119. doi: 10.3892/ijo.2023.5567, PMID 37654171

Alalawy AI. Key genes and molecular mechanisms related to paclitaxel resistance. Cancer Cell Int. 2024;24(1):244. doi: 10.1186/s12935-024- 03415-0, PMID 39003454

Al-Thubiani WS. The role of P-glycoprotein (P-GP) in cancer multidrug resistance (MDR): Challenges for inhibiting P-GP in the context of overcoming MDR. J Pharm Res Int. 2023;35(23):44-58. doi: 10.9734/ jpri/2023/v35i237422

A. M. H.V., Namboori PKK. Design and development of a pharmacogenomic model for breast cancer to study the variation in drug action and side effects. Int J Appl Pharm. 2022;14(3):61-68.

Dwipoyono B, Choirunisa S, Nadjib M, Sjaaf AC. Cost analysis of taxane-based and cisplatin-based chemotherapy regimens for epithelial ovarian cancer in Dharmais national cancer hospital. Int J Appl Pharm. 2017;9:172-175.

Handayani F, Fitria N, Sari YO, AA. Impact of the combination of doxorubicin, cyclophosphamide, and docetaxel on CA 15-3 biomarker levels in breast cancer patients: A comparative study between delayed and non-delayed chemotherapy. Int J Appl Pharm. 2025;17(1):82-88. doi: 10.22159/ijap.2025.v17s1.12

Hemant K, Raizaday A, Sivadasu P, Uniyal S, Hemanth Kumar S. Cancer nanotechnology: Nanoparticulate drug delivery for the treatement of cancer. Int J Pharm Pharm Sci. 2015;7(3):40-46.