The Use of Carboranes in Cancer Drug Development

Abstract

Over the past decade, there has been a rising interest in the use of carboranes as a potential pharmacophoric moiety in the development of new drugs for the treatment of various types of cancer. The unique physical and chemical properties of carboranes make their use attractive in drug development. In several instances, the inclusion of carboranes into a drug structure has increased the agent’s binding affinity, potency, or bioavailability. The purpose of this review is to highlight applications of carboranes to the medicinal chemistry of cancer. Citation: Mason EOZ, Mason CA, Lee Jr MW (2019) The Use of Carboranes in Cancer Drug Development. Med Chem (Los Angeles) 9: 044-055. doi: 10.4172/21610444.1000534 Med Chem (Los Angeles), an open access journal ISSN: 2161-0444 Volume 9(4): 044-055 (2019) 45 typically be used to synthesize any of the three carborane isomers, while in contrast the synthesis of the ortho, meta, and para isomers in aryl rings is much more challenging [5]. The closo-carboranes are both air and moisture stable and are known to possess “superhydrophobicity.” Their high partition coefficient values are known to surpass common bioisosteres such as aryl, cycloalkyl, and adamantyl groups [5]. Moreover, their high stability and low toxicity towards cells make them interesting compounds for therapeutic applications [2]. The interactions between carborane pharmacophores and the active sites of biological targets are often stronger than those of the aryl, cycloakyl, or adamantyl pharmacophore counterparts. Several studies have been performed in an attempt to elucidate the underlying mechanism behind these interactions. In addition to the three dimensional shape and hydrophobicity which results in more points of interaction with the active site, the carborane cage can form dihydrogen bonds. The formation and characteristics of the dihydrogen bonds were explored by Fanfrlik et al. through the use of molecular dynamic simulations between carboranes and various amino and nucleic acids [28]. Dihydrogen bonding, also named proton-hydride bonding, typically occurs between a positively charged hydrogen atom of a proton donor AH (A=N, O, S, C, halogen) and an MH proton acceptor (M=boron, alkali metal, or transition metal). In the case of carboranes and biological molecules these bonds form between NH--HB, CH--HB, and SH--HB. Such bonds are calculated to exhibit strong stabilization energies between 6.1 to 7.6 kcal mol-1, compared with 1 to 5 kcal mol-1 for typical biomolecular hydrogen bond strengths, and H--H distances between 1.7 to 2.2 Å [28]. These interactions can potentially be used to improve the binding of carboranes over the more conventional pharmacophores containing aromatic groups such as aryl, or cycloakyl, or adamantyl. The successful design and implementation of a pharmacophore requires a careful study of the drug candidate’s pharmacokinetics. In cancer therapy, the agent’s biodistribution is an especially important characteristic. The design and use of carborane containing pharmacophores is a relatively recent endeavour [29-31]. Past research efforts described in the literature explored the design of various carborane-based anti-cancer pharmacophores and their relative potencies. However, a majority of this preliminary work was limited to studies conducted in vitro. Nonetheless, there are some important examples in the literature where carborane containing pharmacophores were successfully translated into small animal models. While these experiments were not associated with cancer, it is interesting to note that the enzyme Nampt is highly implicated in many different cancers, including the most aggressive and the most refractory to treatment [32]. Much of what is known regarding the administration, biodistribution, tumor targeting and in vivo stability of carborane derivatives is derived from studies where carboranes were used to develop boron-rich agents for BNCT [7-13]. The concentration of boron required for effective BNCT is several orders of magnitude higher than those typically administered during conventional chemotherapy. However, many of the observations made during BNCT animal studies are still highly relevant to the use of carboranes as a pharmacophore in conventional drugs. Carboranes and substituted carboranes have been observed to be highly stable in vivo. For example, the molecule 2,4-(α,βdihydroxyethyl) deuteroporphyrin (BOPP) is a porphyrin bearing four ortho-carboranyl moieties attached through ester linkages [33]. Several animal studies have been conducted using this molecule, most often using isotonic saline solutions of the potassium salt at a concentration of 10 mg/ml [33]. Solutions of BOPP containing BNCT-relevant doses, typically between 5-50 mg/kg, have been administered to both mice and rat models of glioma cancer through intraperitoneal, intravenous, or tail vein injections [34]. In those studies, doses as high as 200 mg/ kg were well tolerated, causing no apparent signs of morbidity and no mortality. In a separate bio distribution study, 35 mg/kg of BOPP in saline was administered to dogs intravenously and the animals were monitored for up to 28 days [35]. The compound exhibited a long plasma half-life and accumulation in liver, lymph nodes, adrenal and kidney was observed. Figure 1: Ortho-(1), meta-(2), para-carborane (3), and nido-carboranes (4-6). Citation: Mason EOZ, Mason CA, Lee Jr MW (2019) The Use of Carboranes in Cancer Drug Development. Med Chem (Los Angeles) 9: 044-055. doi: 10.4172/21610444.1000534 Med Chem (Los Angeles), an open access journal ISSN: 2161-0444 Volume 9(4): 044-055 (2019) 46 Kreimann et al. explored the biodistribution of a carborane containing porphyrin in a therapeutic study using hamster mouth cancer models. In a multidose protocol they determined the boron uptake in a variety of tissues, as well as tumor, including normal mouth tissues, blood, liver, spleen, and brain over the course of several days [36]. They observed statistically significant differences in accumulation between tissues. The tumor/normal tissue maximum mean ratios were 11.9/1 after three days and the tumor/blood ratios of 235/1 after 4 days [36]. Liposomal formulations of carborane based lipid conjugates have also been extensively studied in both mouse xenograft and chemically induced hamster cancer models. For example, suspensions of small, boron-rich unilamellar vesicles were administered to hamsters as intravenous bolus injections and the distribution of boron was measured in several tissues over a 72-hour period [37]. A long plasma half-life was observed (approximately 30 hours), along with high tumor, liver, and spleen accumulations. At 54 hours post injection, both the tumor accumulation and specificity were remarkable, with a tumor/normal surrounding tissue ratio of nearly 28:1 [37]. Boron-rich carboranecontaining oligomers, referred to as Oligomeric Phosphate Diesters (OPDs) were shown to accumulate in tumor tissue when administers to mice bearing EMT6 tumors via tail vein injections [38].