Bandero, Vilmar

Chan, Kit

Corcoran, Claire

Frankish, Neil

O’Driscoll, Lorraine

Sheridan, Helen

Zhang, Tao

English

Arrow@TUDublin

Technological University Dublin ARROW@TU Dublin Articles School of Food Science and Environmental Health 2020 Drug Discovery: Novel Indane Scaffolds with Anticancer Activity Vilmar Bandero Trinity College Dublin, Ireland Tao Zhang Technological University Dublin, tao.zhang@tudublin.ie Kit Chan Trinity College Dublin, Ireland Lorraine O’Driscoll Trinity College Dublin, Ireland Claire Corcoran Trinity College Dublin, Ireland See next page for additional authors Follow this and additional works at: https://arrow.tudublin.ie/schfsehart  Part of the Life Sciences Commons Recommended Citation Bandero-Filho, V.C., Zhang, T., Chan, K., O’Driscoll, L., Corcoran, C., Frankish, N. and Heridan, H. Drug discovery: Novel indane scaffolds with anticancer activity. IACR AGM, Salthill, Galway. 27-28 Feb 2014. This Conference Paper is brought to you for free and open access by the School of Food Science and Environmental Health at ARROW@TU Dublin. It has been accepted for inclusion in Articles by an authorized administrator of ARROW@TU Dublin. For more information, please contact yvonne.desmond@tudublin.ie, arrow.admin@tudublin.ie, brian.widdis@tudublin.ie. This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License Authors Vilmar Bandero, Tao Zhang, Kit Chan, Lorraine O’Driscoll, Claire Corcoran, Neil Frankish, and Helen Sheridan This conference paper is available at ARROW@TU Dublin: https://arrow.tudublin.ie/schfsehart/350  Bandero-Filho VC,  Zhang T, Chan K,  O’Driscoll L, Corcoran C, Frankish N1  and Sheridan H1  Drug Discovery Group. School of Pharmacy and Pharmaceutical Sciences Trinity College Dublin, Dublin 2, Ireland  Background Bibliography Conclusion and Perspectives:  We have identified a novel chemical scaffold, that demonstrates cytotoxic activity in vitro in a range of human cell lines, including MCF7 and SKBR3 (Breast), DU145 (Prostate) and A549 (Lung). Our working hypothesis has been that hybridization of several bioactive fragments results in synergized bioactivity (Figure 2 and 3). The results demonstrate the validity of this hypothesis, showing that the nature and position of substitution together with stereo-isomeric specificity results in significant increases in bioactivity: e.g. coupling of indan-1-one (IC50 100 micromolar in SKBR3, A549, MCF7 and IC50 40.88 micromolar in DUI45) with fragment A (IC50 100 micromolar in SKBR3 and MCF7; and IC50 46.4 micromolar in A549, and IC50 33.54 micromolar in DU145) yields a novel chemical scaffold with (IC50 1.04 micromolar in SKBR3, 14.9 in A549, 32.1 in DUI145 (Prostate) and 30.5 in MCF7. One hybrid 14b2t compares well with Tamoxifen across the cell lines. Several hybrids are more potent in the SKBR3 cell line. Future chemical synthesis: We are working to couple indanone nuclei with new fragments we have prepared,  that display nanomolar activity across the four cell lines, to generate what we believe will be derivatives with significant nanomolar dual activities. Future bioactivity evaluation: Initial studies also support the tubulin binding effects of scaffolds. This activity will be further evaluated in collaboration with the CNRS , Gif-Sur=Yvette in March. In addition  P-glycoprotein (P-gp) modulating activity will be evaluated. A series of indebt in vitro anticancer assessments and in vivo and in vitro antiinflammatory studies will be carried out over the next six months, to establish MOA and selectivity of these scaffolds.  Drug discovery: Novel indane scaffolds                        with anticancer activity . The indane scaffold is of key importance in the natural world. It occurs in a range of biologically active natural products. The natural structures range from simple indanes and indanones with antibacterial activity e.g. indanone 1 isolated from the cyanobacterium Nostoc 1 to the pterosin family of fern and fungal metabolites e.g. 2, which show cytotoxicity toward the Human leukaemia HL-60 cell line 2, 3, to oligomers of resveratrol (3,5,4‘-trihydroxystilbene) e.g. the indane Pauciflorol F isolated from the Dipterocarpaceae.4 The therapeutic potential of indanes becomes more evident in the area of medicinal chemistry where this scaffold is incorporated into structures that demonstrate therapeutic properties e.g. the indanone Sulindac (Clinoril™; Merck), a non-steroidal anti-inflammatory that has recently demonstrated anti-proliferative and apoptotic effects.5,6 More recently the tubulin polymerisation inhibitor Indanocine (NIH) has been receiving attention.7 During the course of our research on indane monomers and dimers, we have noted that the potential of novel indane scaffolds for the treatment of inflammatory disease and cancer has not been fully exploited. Inflammatory disease is responsible for, or implicated in, a wide range of conditions including, but not limited to, Rheumatoid Arthritis, Cardiovascular Disease, Multiple Sclerosis, inflammatory bowel disease (IBD) and Psoriasis. It is also well established that inflammation plays a significant role in the development of cancer.8  The aim of this research project is to combine, experience led and evidence based, theories with our knowledge of small molecule drug development to generate novel hybrid scaffolds with therapeutic potential for the treatment of cancer and inflammatory disease. The second fragment of interest, in this study comes from the naturally occurring benzophenones.9 This class of molecules features widely in plants used as anti-tumour agents in Traditional Herbal Medicinal systems. A range of bioactivities has been established for members of this chemical class, including tubulin binding and P-glycoprotein (P-gp) modulating activity, the prototypical efflux transporter, implicated in multidrug resistance (MDR).10 RR RRRRINDANE COREANTI-INFLAMMATORY/IMMUNOMODULATORYFRAGMENTAdditional fragment forming new scaffoldNaturally occurring Indane structures 1. Jaki, B.; Orjala, J.; Burgi, H.R.; Sticher, O. Pharmaceutical Biology, 1999. 37(2): 138-143. 2. Chen, Y.H.; Chang, F.R.; Lu, M.C.; Hsieh, P.W. et al. Molecules, 2008. 13(2): 255-266. 3. Donnelly, D.M.X.; O’ Reilly, J.; Polonsky, J.; Sheridan, M.H. Journal of the Chemical Society-Perkin Transactions 1, 1987(8): 1869-1872. 4. Tetsuro, I., Toshiyuki, T., Munekazu, I., Ken-ichi, N., et al., J. Nat. Prod., 2004, 67 (6): 932–937.  5. Scheper, M.A.; Nikitakis, N.G.; Chaisuparat, R. et al. Neoplasia, 2007. 9(3): 192-9. 6. Shiff, S.J.; Qiao, L.; Tsai, L.L.; Rigas, B. J Clin Invest, 1995. 96(1): 491-503. 7. Leoni, L. M., Genini, D., Shih, H., Carrera, C. et al., J Natl Cancer Inst., 2000. 92 (3): 217-222. 8. Serhan, C. N., Ward, P. A., Gilroy, G.W., Eds. (2010). Overview - Fundamentals of Inflammation. Publisher: Cambridge University Press.  9. Mantovani, A., Allavena, P., Sica, A., Balkwill, F. Nature, 2008. 454: 436-444.  Results and Discussion Methods:  Synthesis and specific compounds: Will not be discussed at this point. Cell Culture: All the cell lines were maintained in a humid chamber at 37 ºC and 5% CO2 atmosphere. SKBR3  (ATCC HTB-30), MCF7 (ATCC HTB-22), and DU145(ATCC HTB-81) cells were cultured in RPMI-1640 Medium containing 10% fetal bovine serum (FBS) and 1% L-Glutamine. A549 (ATCC CCL-185) lung carcinoma cells were grown in Dulbecco′s Modified Eagle′s Medium supplemented with 5% FBS. Acid Phosphatase assay: After 5 days of incubation of cells with the drugs, the medium was removed and each well was washed with 100 μL of PBS. Then, 100 μL of freshly prepared phosphatase substrate (10 mM p-nitrophenol phosphate, Sigma) in 0.1 M sodium acetate (Sigma), 0.1 % triton X-100 pH5.5 (BDH) was added to each well. The plates were wrapped in tin foil and incubated in the dark at 37º C for 1 hour. The reaction was stopped by the addition of 50 μL of NaOH 1 M to each well and measuring was obtained in a dual beam plate reader at 405 nm with a reference wavelength of 620 nm. Figure 3: Cytotoxicity of lead hybrids compared with Tamoxifen A novel scaffold designed around an indane nucleus was identified as the chemical target in this study (Figure 1). The scaffold was synthesised by combining a series of small chemical fragments using a range of spacer molecules. A second fragment incorporated into the molecule is centered on the small naturally occurring bioactive benzophenone moiety, which depending on substitution pattern demonstrates a variety of biological properties. Initial studies have led to the development of a synthetic approach that has thus far yielded eight final products with the desired final chemical scaffold. All products and intermediates have been characterized spectroscopically.  The cytotoxicity of the starting fragments was evaluated using the Acid Phosphatase assay, in a series of in vitro cancer cell lines: MCF7 and SKBR3 (Breast), DUI145 (Prostate) and A549 (Lung). The individual fragments displayed low levels of cytotoxicity (Table 1) in A549, MCF7 and SKBR3 cell lines, but do have low micro-molar activity in the DU145. Some fragments with significant cytotoxicity (in red, Table 1) have been prepared and await coupling. Coupling of the main molecular fragments and spacers gave rise to a series of compounds with a novel chemical scaffold. These molecules displayed significant increases in IC50 values in the cell lines under investigation, relative to their component fragments (Figure 2). Initial and ongoing studies have demonstrated inhibition of tubulin binding at micro molar levels.  Pteridophyta    Dipterocarpaceae Figure 1: Target Hybrid Scaffold SKBR31-IND BP 0040100200300**##IC50 (M)A5491-IND BP 0040100200300***###IC50 (M)DU1451-IND BP 0040100200300***###IC50 (M)MCF71-IND BP 00405001000**##IC50 (M)Cytotoxicity of  composite fragments and first hybrid in four cell lines SKBR31-IND 4-OCH3-BP 014b2t0100200300**##IC50 (M)A5491-IND 4-OCH3-BP 014b2t0100200300***##***IC50 (M)DU1451-IND 4-OCH3-BP 014b2t0100200300***###IC50 (M)MCF71-IND 4-OCH3-BP 014b2t05001000*****IC50 (M)Figure 2: Modification of one fragment increased activity of hybrid all cell  lines Fragments IC50 MCF7 M SKBR3 M A549 M DU145 M > 100 > 100 > 100  40.88 > 100  > 100  > 100  28.41 > 100  > 100  46.42 33.50 > 100  > 100  56.63 19.74 > 100  > 100  26.60 24.52 ***8.73 nM 379 nM 29.8 nM  11.7 nM  ***35.4 nM 514 nM 17.4 nM   6.16 nM OOOCH3OCH3H3COOCH3H3COOCH3OH3COH3COOCH3OHTable 1: Cytotoxicity of some fragments before coupling  to form hybrids  ***Fragments have been synthesised and await coupling. We expect significant increases in activity for the final hybrids. ClOOOOCH3H3COH3COOCH3SKBR3SulindacTamoxifen004011c011t012c012t015014b2t014b2c018b4018b50460100200300400500* **** ***** *** *** *** *********### ### #######IC50 (M)A549SulindacTamoxifen004011c011t012c012t015014b2t014b2c018b4018b50460100200300400500** * * ** ** **** ***ns**IC50 (M)DU145SulindacTamoxifen004011c011t012c012t015014b2t014b2c018b4018b50460100200300400500* * ** ** ** ** ** *** ***nsIC50 (M)MCF7SulindacTamoxifen004011c011t012c012t015014b2t014b2c018b4018b50460100200300400500* ***IC50 (M)

Drug Discovery: Novel Indane Scaffolds with Anticancer Activity

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Drug Discovery: Novel Indane Scaffolds with Anticancer Activity

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