Dömling, A., & Hulme, C. (2011). Special issue on Mini-MCR issue and SCS-09--Second International Symposium on Combinatorial Sciences in Biology, Chemistry, Catalysts and Materials. Editorial.. Molecular diversity, 15(1), 1-2.
Hulme, C., & Nixey, T. (2003). Rapid assembly of molecular diversity via exploitation of isocyanide-based multi-component reactions. Current Opinion in Drug Discovery and Development, 6(6), 921-929.
PMID: 14758761;Abstract:
Molecular diversity is the variability of physical properties between molecules, viewed in terms of molecular shape, polarity/charge, lipophilicity, polarizability and flexibility. Due to their widespread medicinal properties, natural products were one of the original sources of molecular diversity; however, new developments in the search for novel pharmacological agents over the last decade have focused on the preparation of chemical libraries as the source of new leads for drug discovery. A plethora of personal synthesizers and new automation technologies have emerged to help fuel the lead discovery engines of drug discovery organizations. Multistep solid-phase syntheses of diverse libraries in excess of 10,000 products can now be prepared via split-and-mix techniques. Simultaneously, a multitude of more efficient, diversity- or target-oriented solution-phase chemical methodologies have appeared in the chemical literature, enabling the relatively facile construction of successful lead generation libraries with low full-time equivalent input and little capital expenditure. Isocyanide-related multi-component reactions hold a pre-eminent position in this regard, and are finding increasing applications in the discovery process of new drugs and agrochemicals. This review is the authors' personal assessment of advances in the field over the last two years (2002 to 2003), with little emphasis placed on highly mechanistic details.
Bell, C. E., Shaw, A. Y., Moliner, F. D., & Hulme, C. (2014). MCRs reshaped into a switchable microwave-assisted protocol toward 5-aminoimidazoles and dihydrotriazines. Tetrahedron, 70(1), 54-59.
Abstract:
A tunable microwave-assisted protocol for the synthesis of two biologically relevant families of heterocycles has been designed. Via a simple switch of reaction conditions, the same starting materials can be engaged in either an improved synthesis of the dihydrotriazine scaffold or a novel, first-in-class MCR to render the challenging 5-aminoimidazole nucleus in a single step. An additional first-in-class MCR is also reported utilizing guanidines to afford 2,5-aminoimidazoles. © 2013 Elsevier Ltd. All rights reserved.
Zhigang, X. u., Moliner, F. D., Cappelli, A. P., Ayaz, M., & Hulme, C. (2014). Expeditious routes to polycyclic molecular frameworks via one-pot, two-step Ugi ring-closing sequences. Synlett, 25(2), 225-228.
Abstract:
A very general and robust multicomponent-reaction protocol involving an Ugi condensation between ethyl glyoxylate, isonitriles, N-Boc-α-amino acids, and mono-N-Boc-protected diamines followed by a series of acid-promoted cyclization steps in a one-pot fashion is reported. This process allows for the assembly of complex polycyclic structures by means of just two simple synthetic operations and a single chromatographic purification in high overall yields. Of note, the first scaffolds derived from a highly Âselective sequence of ring-closing events involving three internal amino nucleophiles is reported. © Georg Thieme Verlag Stuttgart New York.
Martinez-Ariza, G., & Hulme, C. (2015). Recent advances in allosteric androgen receptor inhibitors for the potential treatment of castration-resistant prostate cancer. Pharmaceutical patent analyst, 4(5), 387-402.
Prostate cancer (PC) is the second most frequent cause of male cancer death in the USA. As such, the androgen receptor (AR) plays a crucial role in PC, making AR the major therapeutic target for PC. Current antiandrogen chemotherapy prevents androgen binding to the ligand-binding pocket (LBP) of AR. However, PC frequently recurs despite treatment and it progresses to castration-resistant prostate cancer. Behind this regression is renewed AR signaling initiated via mutations in the LBP. Hence, there is a critical need to improve the therapeutic options to regulate AR activity in sites other than the LBP. Herein, recently disclosed (2010-2015) allosteric AR inhibitors are summarized and a perspective on the potential pharmaceutical intervention at these sites is provided.