Sains Malaysiana 52(11)(2023): 3325-3342

http://doi.org/10.17576/jsm-2023-5211-22

 

Elucidating the Binding Affinity of Meso Porphyrin Derivatives with Bcl-2 through Synthesis and Molecular Docking Analysis

(Elusidasi Kekuatan Ikatan Terbitan Meso Porfirin melalui Analisis Sintesis dan Pendokan Molekul)

 

YASOTHAA RAMAIYAH^1,2, MOHD BAKRI BAKAR³ & MUNTAZ ABU BAKAR^1,*

 

¹Department of Chemical Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor, Malaysia

 ²National Pharmaceutical Regulatory Agency, Ministry of Health Malaysia,

46200 Petaling Jaya, Selangor, Malaysia

³Department of Chemistry, Faculty of Science, Universiti Teknologi Malaysia,

 81310 UTM Johor Bahru, Johor, Malaysia

 

Received: 14 September 2023/Accepted: 4 December 2023

 

Abstract

Reversing multi-drug resistance in a clinical setting remains a formidable issue to date. Porphyrin has high efficiency to conjugate with chemotherapy drugs and effectively deliver within the nucleus of cancer cells which helps in lowering side effect to normal cells. As compared to naturally occurring beta-substituted porphyrins, synthetic meso-substituted porphyrins have numerous benefits. An extensive variety of substituents have been developed with porphyrins. There are eight new porphyrin derivatives synthesised in this research compounds 14-21 which differ from one size to another using Sonogashira and Suzuki coupling techniques. Sonogashira coupling method undergoes a reaction between alkyne terminal sp hybridized carbon and vinyl halide’s sp² carbon in the presence of a Palladium catalyst. Furthermore, Suzuki coupling method has been an effective method in conjugation of aryl halides and borylated porphyrins. The synthesized new compounds were characterized by ultra-violet spectroscopy (UV-Vis), high resolution mass spectrometer (HRMS) and nuclear magnetic resonance (NMR) to confirm successful formation of all new compounds. The docking analysis was performed for compound 14-21. Compounds 16 and 18 showed the greater binding mode at the Bcl-2 protein pocket regards free or metal substituted porphyrin with longer linker chain and less bulky compared to compounds 17 and 19. This study could discover the structure of porphyrin that affects accumulation in cancer cells that potentially transmissible to target tumour.

 

Keywords: Bcl-2 protein; molecular docking; porphyrin; Sonogashira coupling; Suzuki coupling

 

Abstrak

Pemulihan rintangan pelbagai ubat dalam persekitaran klinikal kekal sebagai isu yang sangat kritikal setakat ini. Porfirin mempunyai kecekapan tinggi untuk bergabung dengan ubat kemoterapi dan berkesan menyampaikan ubat dalam nukleus sel kanser dan ini membantu mengurangkan kesan sampingan terhadap sel normal. Terbitan porfirin boleh diaplikasikan dalam pelbagai bidang bergantung kepada penukarganti yang diperkenalkan kepada porfirin. Berbanding dengan beta-porfirin yang wujud secara semula jadi, porfirin yang ditukarganti pada kedudukan meso secara sintetik mempunyai banyak faedah. Pelbagai jenis penukarganti porfirin telah dibangunkan. Terdapat lapan sebatian porfirin baru iaitu sebatian 14-21 yang disintesis dalam penyelidikan ini menggunakan tindak balas penggandingan Sonogashira dan Suzuki. Penggandingan Sonogashira adalah tindak balas antara karbon terhibrid terminal alkuna sp dan karbon vinil halida sp². Manakala, tindak balas Suzuki adalah teknik konjugasi aril halida dan porfirin terborilasi. Sebatian baharu yang disintesis telah dicirikan dengan menggunakan kaedah ultra-lembayung boleh nampak (ULBN), spektrometer jisim resolusi tinggi dan resonans magnet nuklear (RMN). Analisis dok telah dilakukan bagi sebatian 14-21. Sebatian 16 dan 18 menunjukkan mod pengikatan yang lebih besar pada poket protein Bcl-2 iaitu sama ada bebas atau porfirin yang digantikan logam dengan rantai penghubung yang lebih panjang dan kurang besar berbanding kompaun 17 dan 19. Kajian ini menunjukkan bagaimana struktur porfirin mempengaruhi penumpukan dalam sel kanser yang berpotensi untuk dihantar kepada tumor sasaran.

 

Kata kunci: Dok molekul; penggandingan Sonogashira; penggandingan Suzuki; porfirin; Protein Bcl-2

 

REFERENCES

Allouche, A. 2012. Software news and updates gabedit - A graphical user interface for computational chemistry softwares. Journal of Computational Chemistry 32: 174-182.

Bakar, M.A., Sergeeva, N.N., Juillard, T. & Senge, M.O. 2011. Synthesis of ferrocenyl porphyrins via suzuki coupling and their photophysical properties. Organometallics 30(11): 3225-3228.

Barillé-Nion, S., Lohard, S. & Juin, P.P. 2020. Targeting of bcl-2 family members during anticancer treatment: A necessary compromise between individual cell and ecosystemic responses? Biomolecules 10(8): 1-24.

Boscencu, R., Radulea, N., Manda, G., Machado, I.F., Socoteanu, R.P., Lupuliasa, D., Burloiu, A.M., Mihai, D.P. & Ferreira, L.F.V. 2023. Porphyrin macrocycles: General properties and theranostic potential. Molecules 28(3): 1149.

Dahms, K. & Senge, M.O. 2008. Triptycene as a rigid, 120° orienting, three-pronged, covalent scaffold for porphyrin arrays. Tetrahedron Letters 49(37): 5397-5399.

Eom, Y.H., Kim, H.S., Lee, A., Song, B.J. & Chae, B.J. 2016. BCL2 as a subtype-specific prognostic marker for breast cancer. Journal of Breast Cancer 19(3): 252-260.

Fathi, P. & Pan, Di. 2020. Current trends in pyrrole and porphyrin-derived nanoscale materials for biomedical applications. Nanomedicine 15(25): 2493-2515.

Feng, X. & Senge, M.O. 2001. An efficient synthesis of highly functionalized asymmetric porphyrins with organolithium reagents. Journal of the Chemical Society. Perkin Transactions 1(9): 1030-1038.

Gasteiger, J. & Marsili, M. 1980. Iterative partial equalization of orbital electronegativity-a rapid access to atomic charges. Tetrahedron 36(22): 3219-3228.

Giovannetti, R. 2012. The use of spectrophotometry UV-Vis for the study of porphyrins. In Macro to Nano Spectroscopy, edited by Uddin, J. InTech. doi:10.5772/2503

Gujarathi, P. 2020. Review on synthetic advances in porphyrins and metalloporphyrins. International Journal of Chemical Studies 8(3): 23-32.

Han, M. & Zhang, J.Z.H. 2010. Class I phospho-inositide-3-kinases (PI₃K_s) isoform-specific inhibition study by the combination of docking and molecular dynamics simulation. Journal of Chemical Information and Modeling 50(1): 136-145.

Hartnell, R.D., Edwards, A.J. & Arnold, D.P. 2002. Peripherally-metallated porphyrins: meso-η1-porphyrinyl-platinum(II) complexes of 5,15-diaryl- and 5,10,15- triarylporphyrins. Journal of Porphyrins and Phthalocyanines 6(11): 695-707.

Ion, R-M. 2017. Porphyrins and phthalocyanines: Photosensitizers and photocatalysts. In Phthalocyanines and Some Current Applications, edited by Yilmaz, Y. InTech. doi:10.5772/intechopen.68654

Kale, J., Osterlund, E.J. & Andrews, D.W. 2018. BCL-2 family proteins: Changing partners in the dance towards death. Cell Death and Differentiation 25(1): 65-80.

Locos, O.B. & Arnold, D.P. 2006. The Heck reaction for porphyrin functionalisation: Synthesis of meso-alkenyl monoporphyrins and palladium-catalysed formation of unprecedented meso-β ethene-linked diporphyrins. Organic and Biomolecular Chemistry 4(5): 902-916.

Marck, G., Villiger, A. & Buchecker, R. 1994. Aryl couplings with heterogeneous palladium catalysts. Tetrahedron Letters 33(20): 3277-3280.

Mohd Radzuan, N.H., Norazmi, N.A.Z., Ali, A.H., Abu Bakar, M., Agustar, H.K., Mohd Abd Razak, M.R. & Hassan, N.I. 2021. Sintesis, aktiviti antiplasmodium dan kesitotoksikan secara in vitro sebatian porfirin logam ke atas strain Plasmodium falciparum K1. Sains Malaysiana 50(10): 2945-2956.

Mohjer, F., Mofatehnia, P., Rangraz, Y. & Heravi, M.M. 2021. Pd-free, Sonogashira cross-coupling reaction. An update. Journal of Organometallic Chemistry 936: 121712.

Monvall, E. 1976. Statsbudgeten: de stora reformerna gäller arbetslivet. Tidskrift for Sveriges sjukskoterskor 43(2): 54-58.

Morris, J.L., Gillet, G., Prudent, J. & Popgeorgiev, N. 2021. Bcl-2 family of proteins in the control of mitochondrial calcium signalling: An old chap with new roles. International Journal of Molecular Sciences 22(7): 3730.

Nakano, A., Yasuda, Y., Yamazaki, T., Akimoto, S., Yamazaki, I., Miyasaka, H., Itaya, A., Murakami, M. & Osuka, A. 2001. Intramolecular energy transfer in S1- and S2-states of porphyrin trimers. Journal of Physical Chemistry A 105(20): 4822-4833.

Nowak-Krol, A., Plamont, R., Canard, G., Edzang, J.A., Gryko, T., Balaban, T.S., Nowak-krol, A., Plamont, R., Canard, G., Edzang, J.A., Gryko, D.T., Nowak-król, A., Plamont, R., Canard, G. & Edzang, A. 2020. An efficient synthesis of porphyrins with different meso substituents that avoids scrambling in aqueous media. Chemistry 21(4): 1488-1498.

Park, J.M., Hong, K.I., Lee, H. & Jang, W.D. 2021. Bioinspired applications of porphyrin derivatives. Accounts of Chemical Research 54(9): 2249-2260.

Pathak, P., Zarandi, M.A., Zhou, X. & Jayawickramarajah, J. 2021. Synthesis and applications of porphyrin-biomacromolecule conjugates. Frontiers in Chemistry 9(November): 1-30.

Phan, A.T., Kuryavyi, V., Gaw, H.Y. & Patel, D.J. 2005. Small-molecule interaction with a five-guanine-tract g-quadruplex structure from the human MYC promoter. Nature Chemical Biology 1(3): 167-173.

Radzuan, N.H.M., Malek, N.H.A., Ngatiman, M.F., Xin, T.K., Bakar, M.B., Hassan, N.I. & Bakar, M.A. 2018. Synthesis and X-ray single crystal study of 5-(4,4,5,5 – tetramethyl – 1,3,2 – dioxoborolane) – 10,20 – diphenylporphyrin. Sains Malaysiana 47(9): 2083-2090.

Rathi, P.C., Ludlow, R.F. & Verdonk, M.L. 2020. Practical high-quality electrostatic potential surfaces for drug discovery using a graph-convolutional deep neural network. Journal of Medicinal Chemistry 63(16): 8778-8790.

Ryan, A., Gehrold, A., Perusitti, R., Pintea, M., Fazekas, M., Locos, O.B., Blaikie, F. & Senge, M.O. 2011. Porphyrin dimers and arrays. European Journal of Organic Chemistry 29: 5817-5844.

Saini, G., Dalal, V., Savita, B.K., Sharma, N., Kumar, P. & Sharma, A.K. 2019. Molecular docking and dynamic approach to virtual screen inhibitors against Esbp of Candidatus Liberibacter asiaticus. Journal of Molecular Graphics and Modelling 92: 329-340.

Senge, M.O. & Feng, X. 2000. Regioselective reaction of 5,15-disubstituted porphyrins with organolithium reagents - Synthetic access to 5,10,15-trisubstituted porphyrins and directly meso-meso-linked bisporphyrins. Journal of the Chemical Society, Perkin Transactions 1(21): 3615-3621.

Shanmugathasan, S., Johnson, C.K., Edwards, C., Matthews, E.K., Dolphin, D. & Boyle, R.W. 2000. Regioselective halogenation and palladium-catalysed couplings on 5,15-diphenylporphyrin. Journal of Porphyrins and Phthalocyanines 4(3): 228-232.

Van Der Spoel, D., Lindahl, E., Hess, B., Groenhof, G., Mark, A.E. & Berendsen, H.J.C. 2005. GROMACS: Fast, flexible, and free. Journal of Computational Chemistry 26(16): 1701-1718.

Varnado Jr., C.D. & Bielawski, C.W. 2012. 5.08 - Condensation polymers via metal-Catalyzed coupling reactions. Polymer Science: A Comprehensive Reference 5: 175-194.

Yin, L. & Liebscher, J. 2007. Carbon-carbon coupling reactions catalyzed by heterogeneous palladium catalysts. Chemical Reviews 107(1): 133-173.

Zheng, W., Shan, N., Yu, L. & Wang, X. 2008. UV-visible, fluorescence and EPR properties of porphyrins and metalloporphyrins. Dyes and Pigments 77(1): 153-157.

 

*Corresponding author; email: muntaz@ukm.edu.my