Louis M. Rendina

Boron in Drug Discovery: Carboranes as Unique Pharmacophores in Biologically Active Compounds

Boron in Drug Discovery: Carboranes as Unique Pharmacophores in Biologically Active Compounds Fatiah Issa, Michael Kassiou, and Louis M. Rendina* School of Chemistry, The University of Sydney, Sydney NSW 2006, Australia Discipline of Medical Radiation Sciences, Faculty of Health Sciences, The University of Sydney, Cumberland Campus, Lidcombe NSW 2141, Australia Brain and Mind Research Institute, The University of Sydney, Camperdown NSW 2050, Australia

Boronated DNA-Binding Compounds as Potential Agents for Boron Neutron Capture Therapy

Boron Neutron Capture Therapy (BNCT) is a binary cancer treatment that exploits the short range particles released from a nuclear fission reaction involving the non-radioactive 10B nucleus and low-energy (thermal) neutrons for the destruction of tumour cells. If boronated agents are targeted towards chromosomal DNA, the efficiency of BNCT is greatly enhanced. This article presents a concise review of DNA-binding compounds that have been functionalised with boron.

The First CNS-Active Carborane: A Novel P2X7 Receptor Antagonist with Antidepressant Activity

Relative to other polycyclic frameworks (1-3), a carborane cage (4 and Cs·5) exerts a significant biological effect as an inhibitor of the purinergic P2X7 receptor (P2X7R) which allows one to target depression in vivo and thus demonstrate, for the first time, that a carborane has the capacity to modify CNS activity.

The translocator protein (TSPO): A novel target for cancer chemotherapy

The translocator protein (TSPO) is an 18 kDa transmembrane protein primarily found in the outer mitochondrial membrane where it forms a key part of the mitochondrial permeability transition pore (MPTP). Omnipresent in almost all tissues, TSPO up-regulation has been connected to neuronal damage and inflammation, making the protein an important bio-imaging marker for disease progression. More recently, TSPO has attracted attention as a possible molecular target for tumour imaging and chemotherapy. In this review we summarize TSPOs molecular characteristics and highlight research progress in recent years in the field of TSPO-targeted cancer diagnostics and treatments.

Targeting key dioxygenases in tryptophan–kynurenine metabolism for immunomodulation and cancer chemotherapy

Tryptophan to kynurenine metabolism is controlled by three distinct dioxygenase enzymes: tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase 1 (IDO1), and indoleamine 2,3-dioxygenase 2 (IDO2). Collectively, the activity of these enzymes contributes to tumour immune tolerance and immune dysregulation in a variety of disease pathologies, including cancer. Whereas IDO1 inhibitor drug design has been the focus of study for more than two decades (with novel compounds currently in Phase II clinical trials), only recently have the roles of TDO and IDO2 been elucidated in immunosuppression. Consequently, little comparative work on inhibitor cross-reactivity and selectivity has been performed. Here, we provide an overview of the current and future drug discovery landscape for targeting TDO, IDO1, and IDO2 (individually and collectively) for pharmacological intervention.

Selective Aggregation of a Platinum-Gadolinium Complex Within a Tumor-Cell Nucleus**

Gadolinium(III) complexes are widely used in magnetic resonance imaging (MRI) as water relaxation agents to improve image contrast. Therapeutic gadolinium-containing agents are also known in which the metal complex enhances tumor response to chemotherapeutics such as cisplatin, or, more commonly, acts as a radiosensitizer in the treatment of diseases, such as cancer. Gadoliniummay also play an important role in therapeutic techniques, such as synchrotron stereotactic radiotherapy (SSR), in which the selective delivery of gadolinium to the cell nucleus would significantly enhance the efficacy of the treatment. Indeed, De Stasio and co-workers have demonstrated that motexafinGd, a gadolinium(III) complex of the pentadentate texaphyrin ligand, was accumulated by approximately 90% of glioblastoma cell nuclei in vitro, and its potential exploitation as a GdSSR agent is warranted. In recent years, gadolinium complexes have also been explored as potential agents in an experimental anti-cancer treatment known as gadolinium neutron-capture therapy (GdNCT), which is closely related to the well-established boron neutron-capture therapy (BNCT). GdNCTutilizes the non-radioactive Gd isotope (natural abundance 15.7%) in a highly effective thermal neutron-capture reaction to destroy tumor cells. Gd possesses the largest effective nuclear cross-section of all naturally-occurring elements (2.55 10 barns); this value is approximately 66 times greater than that of the B nucleus. Gd undergoes neutron capture to give the products of internal conversion, accompanying Auger and Coster–Kronig (ACK) electron emission and 7.94 MeVof energy. However, the very limited range of ACK electrons means that the gadolinium complex must be localized in close proximity to critical cellular components, such as the cell nucleus, if the neutron capture reaction is to be exploited effectively. The use of gadolinium(III) complexes as potential GdNCT delivery agents to brain tumors has been described, although the feasibility of using archetypal MRI agents such as Gd-DTPA (DTPA= diethylenetriaminepentaacetic acid) in a clinical context for GdNCT is considered unlikely owing to the limited number of tumor-cell nuclei that have been shown to incorporate gadolinium. Indeed, the number of gadolinium compounds reported to date that have a capacity to aggregate selectively in tumor-cell nuclei, for example, is very limited, and the search for new types of gadolinium(III) complexes with high nuclear affinity has recently been proposed. Herein, we present a new Pt-Gd complex that can effectively target the nuclei of tumor cells by means of a functionalized dtpa ligand linked to two {Pt(terpy)} (terpy= 2,2’:6’,2’’-terpyridine) units that have the capacity to bind DNA in an intercalative manner. Based on prior work with analogous Pt–Ln complexes (Ln=La, Nd, Eu), which were designed to act as luminescent probes for DNA recognition, we reasoned that the related Pt-Gd species 1 would have the capacity to deliver gadolinium to this important biomolecule. In this work, we report the first unequivocal example of gadolinium delivery to a tumor-cell nucleus by a platinum complex. Complex 1was prepared in good yield by a similar manner to that described for the analogous Pt-Ln species (Ln=La, Nd, Eu; Scheme 1). The convenient one-pot synthesis of 1 demonstrates the high affinity of the soft Pt and hard Gd cations for the soft and hard Lewis bases (S and N/O, respectively) that are present in the functionalized DTPA ligand. The purple Pt-Gd complex has excellent solubility and stability in aqueous solution, and no evidence was found for the loss of Pt or Gd ions from 1, even after 24 h of standing in a buffered pH 7.4 solution at room temperature. Preliminary DNA thermal denaturation (DNA melting) experiments involving calf-thymus DNAwere performed on 1 at pH 7.4 (Supporting Information, Figure S1). There exists a significant difference in the melting temperatures between the freeand drug-treated DNA samples (DTm= 4.5 0.5 8C), [*] Dr. E. L. Crossley, Dr. J. B. Aitken, Prof. L. M. Rendina School of Chemistry, The University of Sydney Sydney, NSW 2006 (Australia) Fax: (+61)2-9351-3329 E-mail: rendina@chem.usyd.edu.au

The Fifth Element in Drug Design: Boron in Medicinal Chemistry

The unique chemistry of boron allows for the utilisation of novel building-blocks which are not traditionally found in medicinal chemistry. The pharmaceutical industry has begun to exploit boronic acid derivatives as new drugs and several research groups are also exploring 1,2-azaborines and icosahedral boranes known as carboranes as boron-based structural motifs, with great promise for innovative drug design. Recent advances in the medicinal chemistry of these three important boron moieties are highlighted and illustrated with selected examples.

Cationic platinum(II) complexes: platinum–alkyl bond cleavage by a powerful Lewis acid

Treatment of [PtCl(Me)(dbbipy)] or [PtCl2(dbbipy)](dbbipy = 4,4′-di-tert-butyl-2,2′-bipyridine) with AgX (X = SO3CF3 or O2CCF3) gave the complexes [PtMe(SO3CF3)(dbbipy)]1, [Pt(SO3CF3)2(dbbipy)]2 and [Pt(O2CCF3)2(dbbipy)]5. The complexes [PtCl(SO3CF3)(dbbipy)]3 and [PtMe(O2CCF3)(dbbipy)]4 were prepared by the addition of HX to [PtCl2(dbbipy)] or [PtMe2(dbbipy)], respectively. Complex 1 reacted with CO to give the cationic carbonyl complex [PtMe(CO)(dbbipy)][SO3CF3]6a, which reacted with NEt2H to give an equilibrium with the corresponding carbamyl complex [Pt(CONEt2)Me(dbbipy)]7. In the first example of alkyl-ligand abstraction from a late-transition-metal complex by the powerful Lewis acid B(C6F5)3, the complexes [PtMeL(dbbipy)][BMe(C6F5)3](L = CO 6b or C2H48) were readily prepared from [PtMe2(dbbipy)] and B(C6F5)3 in the presence of L.

Multinuclear platinum(II)-amine complexes containing bis(aminopropyl)dicarba-closo-dodecaborane(12) ligands

Treatment of the bridging bidentate 1,Z-bis(aminopropyl)-1,Z-dicarba-closo-dodecaborane(12)(1,Z-bis(aminopropyl)-1,Z-carborane) ligands of the type 1,Z-[H(2)N(CH(2))(3)](2)-1,Z-C(2)B(10)H(10)(L(1), Z= 7, 5) or (L(2), Z= 12, 6) with two equivalents of trans-[PtClI(2)(NH(3))](-), followed by halogen ligand metathesis with AgOTf and HCl((aq)) afforded the novel diplatinum(II)-amine species cis-[[PtCl(2)(NH(3))](2)L(n)](7(n= 1) or 8(n= 2), respectively). Similarly, the reaction of L(1) or L(2) with the labile trans-[PtCl(dmf)(NH(3))(2)](+) afforded trans-[[PtCl(NH(3))(2)](2)L(n)](OTf)(2)(9(n= 1) or 10(n= 2), respectively) in good yield and purity. However, isolation of the analogous 1,2-carborane complexes was not possible owing to decomposition reactions that led to extensive degradation of the carborane cage and reduction of the metal centre. The mixed dinuclear complex [cis-[PtCl(2)(NH(3))]-L(1)-trans-[PtCl(NH(3))(2)]]OTf (19) was prepared by treatment of the Boc-protected amine ligand 1-[(Boc)(2)N(CH(2))(3)]-7-[H(2)N(CH(2))(3)]-1,7-C(2)B(10)H(10)(L(3), 15) with trans-[PtCl(dmf)(NH(3))(2)](+) to yield trans-[PtCl(NH(3))(2)L(3)]OTf (16), followed by acid deprotection of the pendant amine group, complexation with trans-[PtClI(2)(NH(3))](-), and halogen ligand metathesis using AgOTf and HCl((aq)). A novel trinuclear species containing 5 was prepared by the addition of two equivalents of 15 to the labile precursor cis-[Pt(dmf)(2)(NH(3))(2)](2+) followed by acid deprotection of the pendant amine groups. Further complexation with two equivalents of trans-[PtClI(2)(NH(3))](-) followed by halogen ligand metathesis using AgOTf and HCl((aq)) afforded the triplatinum(II)-amine species [cis-[Pt(NH(3))(2)(L(1))(2)]-cis-[PtCl(2)(NH(3))](2)](OTf)(2)(23). Complexes 7-10, 19 and 23 represent the first examples of multinuclear platinum(ii)-amine derivatives containing carborane cages. Preliminary in vitro cytotoxicity studies for selected complexes are also reported.

Synthesis and DNA-binding properties of dinuclear platinum(ii)–amine complexes of 1,7-dicarba-closo-dodecaborane(12)Electronic supplementary information (ESI) available: experimental section. See http://www.rsc.org/suppdata/cc/b1/b108081d/

The first examples of platinum(II)-amine complexes containing a dicarba-closo-dodecaborane(12) (carborane) moiety are described; preliminary in vitro DNA-binding experiments indicate that the complexes are capable of targetting plasmid DNA.