*2.2.1. Implications for drug discovery: structural features of closo-carboranes and metallacarboranes. How do they influence on the drug-like properties?*

The most known and commonly used class of polyhedral boron compounds in the medicinal chemistry field are the icosahedral dicarba-*closo*-dodecaborane (C2 B10H12) commonly referred to as carboranes which exist in three isomeric forms named with respect to the positioning of the two CH vertices (**Figure 4**): 1,2- or *ortho*- (**1**); 1,7- or *meta*- (**2**); and 1,12- or *para*-carborane (**3**); to a lesser extent, their mono-anionic derivatives resulting from the loss of a B vertex, commonly known as *nido*-carborane (**4** [C2 B9 H12]<sup>−</sup> ); and their metal complexes known as metallacarborane (**5** [M(C2 B9 H11) 2 ]− , where M is a metal) that are generated after removal of the bridge hydrogen from the *nido*-carborane (**Figure 4**) [29, 30].

Among the outstanding and widely explored properties of carboranes and metallacarboranes for medicinal chemistry research are (a) the geometry and the electron-deficient nature of the boron atoms, which generate a strong hydride character in the BH shell, which are some of the main features that determine the intermolecular interactions with the biological targets because they make the B-clusters extremely hydrophobic; (b) both the pharmacokinetics and the bioavailability can be modulated according to the chemotype of boron cluster selected, so the hydrophilicity and lipophilicity, or both, could be tuned; (c) the globular architecture and rigid geometry allow for molecular construction in three dimensions improving the docking, or not, with bio-targets; (d) high boron content per molecule and stability to catabolism are important criteria for the development of agent for BNCT; and (e) the well-established chemistry that makes boron clusters attractive synthons to construct novel pharmaceuticals [31].

Nevertheless, some problems persist today that delay the application of boron clusters in the development of new drugs: (a) the relatively high cost of carboranes and their derivatives even more if they will be used in BNCT because 10B-enriched compound will be needed; (b) the difficulty of in silico drug design and screening of boron cluster drugs, due to the lack of appropriate descriptors for the interaction potentials of boron and the attached hydrogen atoms; and (c) the lack of libraries of boron cluster compounds for high-throughput screening.

to glycohydrolases, which bind to tumor-associated antigens, through the glucosidic bond

**Figure 4.** (A) Numbering and nomenclature of the *closo*-carborane systems. Synthesis of *meta* and *para*-carborane derivatives from the *ortho*-carborane isomer through thermal isomerization. (B) Partial degradation of *ortho-*, *meta-*, and *para*-carborane and numbering of nido-carborane system according to IUPAC. (C) Synthesis of metallacarborane from

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On the other hand, in the last few years, boron-bearing purines, pyrimidines, thymidines, nucleosides, and nucleotides have been widely explored as a novel approach to improve boron uptake in glioma tumor cells. This strategy is based on the fact that tumor cells have higher metabolic activity and an increased requirement for DNA and RNA precursors [39, 40]. Although in recent years several strategies have been addressed, the main focus has been on thymidine analogs substituted with *ortho*-carbonyl cluster at the *N*-3 positions (**13** and **14**, named as 3CTAs; **Figure 6**). Both analogs are potential substrates for human thymidine kinase 1 (hTK1), a cytosolic deoxynucleoside kinase of the DNA synthesis salvage pathway that is predominantly found in proliferating cancer cells. The selective accumulation and retention of 3CTAs in tumor cells via a mechanism known as kinase-mediated trapping (KMT) render these molecules as potential BNCT delivery agents against high-grade brain glioma, such as GBM [41–43]. Another considerable attention has also been to metallacarborane, mainly the bis-(dicarbollyl)-cobalt and bis-(dicarbollyl)-iron derivatives (**15**–**17**, **Figure 6**). They can also be selectively accumulated in rapidly multiplying neoplastic cells; following their conversion to the corresponding nucleotides, trapped within the cell; or, ideally, incorporated into nuclear DNA of tumors [44]. Despite this, these compounds still have not studied in gliomas.

Barth and co-workers evaluated 10B-enriched derivative **14**, using the RG2 model as in vivo brain tumor model [45]. First, they demonstrated that derivative **14** efficiently delivers boron atoms in cancer cell, which allowed tumor reduction after BNCT in nude mice bearing tumor induced with TK1 positive cell. In addition, based on these favorable results, BNCT studies carried out in the RG2 rat model lead to an increased in life span (ILS) 2.4× in comparison with L-BPA as control therapy. Nevertheless, the greatest percent ILS (122%) was seen in RG2 glioma-bearing rats that received the combination of derivative **14** and

cleavage and concomitant release of carboranyl moiety in the tumor cell surface.

*nido*-carborane.
