Synthesis and anticancer activity of focused compound libraries from the natural product lead, oroidin

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Abstract

Oroidin (1), (E)-N-(3-(2-amino-1H-imidazol-4-yl)allyl)-4,5-dibromo-1H-pyrrole-2-carboxamide, is a pyrrole alkaloid isolated from the marine sponge Agelas oroides. Routine screening in a panel of twelve cancer cell lines revealed 1 to be poorly cytotoxic with the 50% growth inhibition concentration (GI50) of 42 μM in MCF-7 (breast) cells and 24 μM in A2780 (ovarian) cells and >50 μM in all other cell lines tested. The development of eight focused libraries comprising thirty compounds total identified N-(biphenyl-4-ylmethyl)-1H-pyrrole-2-carboxamide (4l), N-benzyl-4,5-dibromo-1H-pyrrole-2-carboxamide (5a) and N-(biphenyl-4-ylmethyl)-4,5-dibromo-1H-pyrrole-2-carboxamide (5l) as potent inhibitors of cell growth in our panel of cell lines. Of these compounds GI50 values of <5 μM were observed with 4l against HT29 (colon) and SW480 (colon); 5a against HT29; and 5l against HT29, SW480, MCF-7, A431 (skin), Du145 (prostate), BE2-C (neuroblastoma) and MIA (pancreas) cell lines. As a cancer class, colon cancer appears to be more sensitive to the oroidin series of compounds, with analogue 5l being the most active.

Introduction

Natural products and their derivatives account for almost half of all approved drugs with the majority being of terrestrial origin.1, 2 Many marine origin compounds are finding applications as drugs,3, 4 potential drugs,5 neutraceuticals,6 molecular tools,7 cosmeceuticals,8 agrochemicals,9 microbiological media (agar),10 and in the food and pharmaceutical industries.11 In terms of pharmaceuticals some have shown potential as anticancer agents,5 antimicrobials,12 antimalarials13 and application in other medical conditions.14, 15, 16 Our team has a long history of exploring a range of natural product sources as a means to identify and develop novel lead compounds against a range of human diseases.17, 18 Indeed, we have explored natural products targeting malaria, tuberculosis, epilepsy and cancer. In this present study we re-isolated oroidin (1), a natural product first isolated from the sponge Agelas oroides in 1971 and later from several other sponges (Fig. 1).19, 20

Oroidin (1) belongs to the ‘bromopyrrole’ family of alkaloids, characterized by the presence of a brominated pyrrole–imidazole moiety.22, 23 While there are very few reports of the biological activity associated with 1, it does display modest levels of anti-protozoal activity against Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani and Plasmodium falciparum.23 Oroidin has also been used as a lead compound in the development of inhibitors of bacterial biofilm formation.24 We have held a long term interest in the discovery and development of cytotoxic small molecules ranging from cantharidin analogues,25, 26, 27, 28 cytotoxic nitriles through to mechanism based inhibition brought about by dynamin and clathrin inhibitors.29, 30, 31, 32, 33, 34, 35, 36, 37 Given this interest, we screened 1 against our panel of twelve cancer cell lines for growth inhibition (see Table 1 for details). Oroidin displayed 42 and 24 μM potency against MCF-7 (breast) and A2780 (ovarian) carcinoma cell lines, respectively. While only moderately potent at inhibiting cell growth, oroidin’s structural simplicity suggested that rapid elaboration might be possible.

While structurally simple, the reported synthetic routes to oroidin include Pd-mediated coupling with preformed imidazole moieties,38, 39, 40, 41, 42 approaches requiring amino acid precursors43, 44, 45, 46, 47 and olefination strategies.48, 49, 50, 51, 52 More recently Rasapalli et al., reported the use of imidazo[1,2-a]pyrimidines as a heterocyclic surrogate for the polyfunctionalised 2-amino-1H-imidazole nucleus of oroidin, hymenidin and clathordin.53 Takale et al. have also recently reported the synthesis and anti-bacterial activity of oroidin analogues.54 The biosynthesis and synthesis of this natural product containing the pyrrolic ring has been reviewed by Al-Mourabit55 and Young.56 To date all methods of oroidin synthesis found within the literature have been either complex, not stereo-specific and typically low yielding.

Section snippets

Results

As the initial activity of 1 was modest we examined structural modifications; however, current literature approaches were viewed as too complex for focused library development, validation and potential enhancement of the cytotoxicity of oroidin-based analogues, even though the recent synthesis by Rasapalli now allowed for more rapid access into the oroidin scaffold.53 Adopting a simpler approach we viewed 1 as comprising three modifiable regions (A) the pyrrole moiety tail group, (B) a central

Conclusions

Herein we have synthesized thirty analogues of the natural product oroidin (1). Screening of these compounds against a panel of twelve cancer cell lines, initially at a drug concentration of 25 μM, with subsequent dose response evaluation for those with noteworthy levels of cell death identified a number of promising cytotoxic compounds. Of the thirty analogues seven (4l, 5a, 5e, 5f, 5h, 5k and 5l) proceeded to full dose response evaluation. The lead compound, oroidin (1), was also evaluated and

General techniques and instrumentation

All reagents were purchased from Sigma Aldrich, Matrix Scientific, AK Scientific, and Merck Scientific, and used without further purification unless otherwise stated.

1H and 13C NMR spectra were recorded on a Bruker Avance™ AMX 400 MHz spectrometer at 400.13 and 100.62 MHz, respectively. Spectra were recorded using deuterated acetone (Acetone-d6) and deuterated dimethylsulfoxide (DMSO-d6), as specified. For acetone-d6 the residual solvent peaks were used as the internal reference [δ 2.05 (quintet)

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