Synthesis and functionalization of nitrosyl rhenacarboranes towards their use as drug delivery vehicles

Abstract

The compound [3,3,3-(CO) 3 -closo-Re(8-O(CH 2 ) 2 OCH 2 CH 2 -3,1,2-C 2 B 9 H 10 )] has been synthesized and used as precursor to several nitrosyl rhenacarborane complexes with boronbound B-O(CH 2 ) 2 O(CH 2 ) 2 -tethers to halo, amino and hydroxo functional groups. The last two in particular have afforded a pair of rhenacarborane derivatives, [3,3-(CO) 2 -3-NO-closo-Re(8-O(CH 2 ) 2 O(CH 2 ) 2 NH 3 -3,1,2-C 2 B 9 H 10 )]BF 4 and [3,3-(CO) 2 -3-NO-closo-Re(8-O(CH 2 ) 2 O(CH 2 ) 2 OH-3,1,2-C 2 B 9 H 10 )], for potential use as drug-delivery vehicles. Bioconjugates tethering our delivery vehicles to amino acids or small peptides that are not readily transported across the blood-brain barrier, either by means of membrane-based transport mechanisms or through passive diffusion, could make potential pharmacological agents for central nervous system infiltration. The final nitrosyl complexes are made following nucleophilic ring opening of the β-boron-bound 1,4-dioxane moiety and our work has established that even with unprotected hydroxo and amino terminal groups, the metal can be selectively nitrosylated using [NO] [BF 4 ] without destroying the integrity of the B-O(CH 2 ) 2 O(CH 2 ) 2 X (X = OH, NH 3 ) tether.

Neutral Rhenadicarbaboranes with Re(CO)2(NO) Vertices: A Theoretical Study of Building Blocks for Rhenacarborane-Based Drug Delivery Agents

“…Such regioselective functionalization has been shown to work with all classes of bioactive substances, including aminoacids, lipids, and nucleosides, as well as incorporation into dendrimers, liposomes, and other biocompatible methods of nanoencapsulation [1]. In this connection carboranes also provide two specific advantages: the presence of boron, which allows for radiotherapeutical techniques such as boron neutron capture therapy (BNCT), and the availability of viable syntheses leading to endo-substitution with transition metal synthons to yield metallacarboranes [1][2][3][4][5][6][7][8][9].…”

“…Such molecules have the remarkable property of passing the blood-brain barrier with the hydrophobicity of the carborane and the charge-neutral character of the nitrosyl/carbonyl-metal moiety being essential towards achieving this goal. Such observations suggest clear potential for therapeutic agents directed within the central nervous system either by delivering radioactive material via the substituents of the carborane system, or by delivering other conjugated therapeutic agents which would not otherwise pass the blood-brain barrier, such as peptides [1,7]. Also, when rhenacarboranes are compared to their technetium analogs, they complement their lack of radioactivity with a useful degree of luminescence with a potential for in vitro and in vivo imaging.…”

“…Also, when rhenacarboranes are compared to their technetium analogs, they complement their lack of radioactivity with a useful degree of luminescence with a potential for in vitro and in vivo imaging. The latter, correlated with the distinct affinity for biological targets such as the estrogen receptor, has fueled further synthetic interest into rhenacarboranes and into their biologically-relevant reactivity, structure and stability [1][2][3][4][5][6][7][8][9]. The chemistry of such rhenacarboranes dates back to the 1965 synthesis of the icosahedral dicarbaborane rhenium carbonyl monoanion [3,1,2-C 2 B 9 H 11 Re(CO) 3 ] − as its cesium salt [16,17].…”

“…The chemistry of such rhenacarboranes dates back to the 1965 synthesis of the icosahedral dicarbaborane rhenium carbonyl monoanion [3,1,2-C 2 B 9 H 11 Re(CO) 3 ] − as its cesium salt [16,17]. Replacement of one of the carbonyl groups in [3,1,2-C 2 B 9 H 11 Re(CO) 3 ] − with NO + gives the neutral 3,1,2-C 2 B 9 H 11 Re(CO) 2 (NO) originally synthesized by Stone and co-workers [18] but then later used by Jelliss and coworkers as a building block for their work on rhenacarborane-based drug delivery agents [1,7]. Related neutral rhenacarborane derivatives include the tricarbaborane derivatives (C 3 B n−4 H n−1 )Re(CO) 3 , which are direct analogues of the stable (η 5 -C 5 H 5 )Re(CO) 3 .…”

Deviations from the Most Spherical Deltahedra in Rhenatricarbaboranes Having 2n + 2 Wadean Skeletal Electrons

“…In the latter connection, replacement of one CO group by the isoelectronic NO + group gives the neutral rhenium carbonyl nitrosyl derivative 3,1,2-C 2 B 9 H 11 Re­(CO) 2 (NO). This nitrosyl system has been used as the parent system for the synthesis of carborane derivatives as drug delivery vehicles by Jelliss and coworkers …”