The evolution of bisindolyl maleimides and indolyl maleimide derivatives and their unique biological activities have stimulated great interest in medicinal chemistry programs. Bisindolylmaleimide (BIM)-type compounds arise from natural sources such as arcyriarubin and are biosynthetically related to indolocarbazoles. BIMs are commonly the immediate synthetic precursors of indolocarbazoles, lacking a central bond between the two aromatic units and making them more flexible and drug-like. Synthetic endeavours within this class of compounds are broad and have led to the development of both remarkably potent and selective protein kinase inhibitors. Clinical BIM examples include ruboxistaurin and enzastaurin, which are highly active inhibitors of protein kinase C-β. While BIMs are widely recognised as protein kinase inhibitors, other modes of activity have been reported, including the inhibition of calcium signalling and antimicrobial activity. Critically, structural differences can be used to exploit new bioactivity and therefore it is imperative to discover new chemical entities to address new targets. BIMs can be highly functionalised or chemically manipulated, which provides the opportunity to generate new derivatives with unique biological profiles. This review will collate new synthetic approaches to BIM-type compounds and their associated bioactivities with a focus on clinical applications.

The synthesis and biological evaluation of a series of novel heterocyclic indole derivatives is described. The consolidation of the combretastatin and bisindolylmaleimide templates towards the inclusion of a novel heterocyclic ring proffered a versatile pharmacophore with which to pursue chemical diversification. Given literature precedent, maleimide was initially investigated in this role and the bioactivity assessed by measurement of NCI-60 cell panel growth. Subsequently, a range of 5-aminopyrazoles was designed and developed to explore the specific effect of heterocycle hydrogen bonding on cell growth. The unique electronic nature of the 5-aminopyrazole moiety allowed for regiospecific monosubstitution on different sites of the ring, such as thiourea substitution at the N(1) position for derivative 45 or trifluoroacetylation on the 5-amino position for 43. Further derivatisation led to the ultimate development of bicyclic pyrazolotriazinedione 41 and pyrimidine 42 systems. The antiproliferative activities of these 3,4-diaryl-5-aminopyrazoles were assessed using the NCI-60 cell screen, disclosing the discovery of distinct selectivity profiles towards a number of cell lines, such as SNB-75 CNS cancer, UO-31 and CAKI-1 renal cancer cells. A series of DNA topological assays discounted the interaction with topoisomerase II as a putative mechanism of action.

Cancer causes about 13% of all human deaths and at least one fifth of all deaths in Europe and North America.¹ Although chemotherapy is increasingly prescribed, it is not without side effects and so new, more selective remedies for cancer sufferers must be found. Since the discovery of the anticancer properties of the indolocarbazole staurosporine, many analogues have been synthesised in order to obtain compounds that have a higher potency with respect to anticancer mechanisms.^{2, 3} The overall objective of this project is to produce selective and highly potent novel anticancer agents through modification of the indolocarbazole structure and a focus of this work is the replacement of the lactam/maleimide heretocycle to form a series of novel indolocarbazole derivatives including the first reported synthesis of a series of novel substituted indolocarbazole uracils. Biological evaluation via the NCI 60 cell line screen has been completed for a number of these compounds with some showing significant selectivity towards individual leukaemia and melanoma cell lines. References GLOBOCAN 2008, database (version 1.2) http://globocan.iarc.fr C. Peifer, T. Stoiber, E. Unger, F. Totzke, C. Schächtele, D. Marmé, R. Brenk, G. Klebe, D. Schollmeyer and G. Dannhardt, J. Med. Chem., Design, Synthesis, and Biological Evaluation of 3,4-Diarylmaleimides as Angiogenesis Inhibitors, 2006, 49, 1271. L. T. Pierce, M. C. Cahill, H. J. Winfield and F. O. McCarthy, Eur. J. Med. Chem., Synthesis and Identification of Novel Indolo[2,3-a]pyrimido[5,4-c]carbazoles as a New Class of Anti-cancer Agents 2012, 56, 292.

The 3,4,5-trimethoxyphenyl moiety is a common motif employed in anticancer drug discovery, due to its prevalence in a variety of important natural products such as Combretastatin. Work undertaken by our group and others has demonstrated that structural diversification of this template can lead to potent anticancer activity. The synthesis and biological evaluation of a series of novel indole-trimethoxyphenyl derivatives are described herein. The consolidation of the combretastatin and bisindolyl templates towards the inclusion of a novel heterocyclic headgroup proffered a versatile pharmacophore with which to pursue chemical diversification. Rationalising the enhancement of existing H-bonding interactions or potential exploitation of new contacts, the introduction of substituted maleimides constituted an overarching theme. This allowed for the evaluation of the effects pertaining to oxygen insertion, extended maleimide substitution and N-functionalisation. Photo-mediated dehydrogenation of a key synthetic intermediate offered access to trimethoxyphenylcarbazoles, representing the first time a panel of such congeners has been reported with further derivatisation also possible. Subsequent evaluation of anticancer activity of the indole-trimethoxyphenyl conjugates utilising the NCI-60 cell screen showed growth inhibitory profiles towards numerous cell lines including: A498 renal, IGROV1 ovarian, DU-145 prostate, SW-620 colon and MCF-7 breast cancer cell lines. The influence of structure on anticancer activity is described.

Glycogen synthase kinase-3 (GSK-3) refers to a group of multifaceted serine/threonine protein kinases that, in mammals, exist as two isoforms (GSK-3a and GSK-3b). Both isoforms share very similar homology but represent contrasting pharmacology. The quest for targeted GSK-3 inhibition has recently become a mainstay for pharmaceutical companies due to the enzymes’ role in a multitude of under-addressed disease states including cancer, Alzheimer’s and bipolar disorder. Herein, we describe the synthesis and evaluation of novel indole derivatives as anticancer agents. A bisindolyl template has been derived, starting from a substituted maleimide, through the introduction of an oxygen atom to the headgroup (hydroxymaleimide). Assessing the bioactivity of these derivatives through kinase assays allowed for the identification of substituent derived selectivity. Following on from this, indole substitution was completed and assessed with the identification of unique selectivity patterns in the GSK-3 and CDK kinase assays. Subsequent evaluation of anticancer activity utilising the NCI-60 cell screen showed growth inhibitory profiles towards a multitude of cell lines including: SNB-75 CNS cancer, A498 and UO-31 renal, MDA MB435 melanoma and a panel of leukemia cell lines. Achieving selective kinase inhibition through modulation of this bisindolyl template is evident and will inform future selective clinical candidates.