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Primary Amine Nucleophilic Addition to Nitrilium Closo-Dodecaborate [B12H11NCCH3]-: A Simple and Effective Route to the New BNCT Drug Design.

ABSTRACT: In the present work, a convenient and straightforward approach to the preparation of borylated amidines based on the closo-dodecaborate anion [B12H11NCCH3NHR]-, R=H, Alk, Ar was developed. This method has two stages. A nitrile derivative of the general form [B12H11NCCH3]- was obtained, using a modified technique, in the first stage. On the second stage the resulting molecular system interacted with primary amines to form the target amidine products. This approach is characterised by a simple chemical apparatus, mild conditions and high yields of the final products. The mechanism of the addition of amine to the nitrile derivative of the closo-dodecaborate anion was studied, using quantum-chemical methods. The interaction between NH3 and [B12H11NCCH3]- ammonia was chosen as an example. It was found that the structure of the transition state determines the stereo-selectivity of the process. A study of the biological properties of borylated amidine sodium salts indicated that the substances had low toxicity and could accumulate in cancer cells in significant amounts.

SUBMITTER: Nelyubin AV

PROVIDER: S-EPMC8707455 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Primary Amine Nucleophilic Addition to Nitrilium Closo-Dodecaborate [B12H11NCCH3]-: A Simple and Effective Route to the New BNCT Drug Design.

Nelyubin Alexey V AV Selivanov Nikita A NA Bykov Alexander Yu AY Klyukin Ilya N IN Novikov Alexander S AS Zhdanov Andrey P AP Karpechenko Natalia Yu NY Grigoriev Mikhail S MS Zhizhin Konstantin Yu KY Kuznetsov Nikolay T NT

International journal of molecular sciences 20211213 24

In the present work, a convenient and straightforward approach to the preparation of borylated amidines based on the closo-dodecaborate anion [B12H11NCCH3NHR]-, R=H, Alk, Ar was developed. This method has two stages. A nitrile derivative of the general form [B12H11NCCH3]- was obtained, using a modified technique, in the first stage. On the second stage the resulting molecular system interacted with primary amines ...[more]

PMID: 34948186

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Project description:Oligonucleotide conjugates with boron clusters have found applications in different fields of molecular biology, biotechnology, and biomedicine as potential agents for boron neutron capture therapy, siRNA components, and antisense agents. Particularly, the closo-dodecaborate anion represents a high-boron-containing residue with remarkable chemical stability and low toxicity, and is suitable for the engineering of different constructs for biomedicine and molecular biology. In the present work, we synthesized novel oligonucleotide conjugates of closo-dodecaborate attached to the 5'-, 3'-, or both terminal positions of DNA, RNA, 2'-O-Me RNA, and 2'-F-Py RNA oligomers. For their synthesis, we employed click reaction with the azido derivative of closo-dodecaborate. The key physicochemical characteristics of the conjugates have been investigated using high-performance liquid chromatography, gel electrophoresis, UV thermal melting, and circular dichroism spectroscopy. Incorporation of closo-dodecaborate residues at the 3'-end of all oligomers stabilized their complementary complexes, whereas analogous 5'-modification decreased duplex stability. Two boron clusters attached to the opposite ends of the oligomer only slightly influence the stability of complementary complexes of RNA oligonucleotide and its 2'-O-methyl and 2'-fluoro analogs. On the contrary, the same modification of DNA oligonucleotides significantly destabilized the DNA/DNA duplex but gave a strong stabilization of the duplex with an RNA target. According to circular dichroism spectroscopy results, two terminal closo-dodecaborate residues cause a prominent structural rearrangement of complementary complexes with a substantial shift from the B-form to the A-form of the double helix. The revealed changes of key characteristics of oligonucleotides caused by incorporation of terminal boron clusters, such as the increase of hydrophobicity, change of duplex stability, and prominent structural changes for DNA conjugates, should be taken into account for the development of antisense oligonucleotides, siRNAs, or aptamers bearing boron clusters. These features may also be used for engineering of developing NA constructs with pre-defined properties.

Project description:In vivo deastatination has been a major problem in the development of reagents for therapeutic applications of the alpha-particle emitting radionuclide (211)At. Our prior studies demonstrated that the use of a closo-decaborate(2-) ([closo-B(10)H(9)R](2-)) moiety for (211)At labeling of biomolecules provides conjugates that are stable to in vivo deastatination. In this investigation, the closo-decaborate(2-) moiety was compared with the structurally similar closo-dodecaborate(2-) ([closo-B(12)H(11)R](2-)) to determine if one has more favorable properties than the other for use in pendant groups as (211)At labeling molecules. To determine the differences, two sets of structurally identical molecules, with the exception that they contained either a closo-decaborate(2-) or a closo-dodecaborate(2-) moiety, were compared with regard to their synthesis, radiohalogenation, stability to in vivo deastatination and tissue distribution. Quite different rates of reaction were noted in the synthetic steps for the two closo-borate(2-) moieties, but ultimately the yields were similar, making these differences of little importance. Differences in radiohalogenation rates were also noted between the two closo-borate(2-) moieties, with the more electrophilic closo-decaborate(2-) reacting more rapidly. This resulted in somewhat higher yields of astatinated closo-decaborate(2-) derivatives (84% vs 53%), but both cage moieties gave good radioiodination yields (e.g., 79-96%). Importantly, both closo-borate(2-) cage moieties were shown to have high stability to in vivo deastatination. The largest differences between pairs of compounds containing the structurally similar boron cage moieties were in their in vivo tissue distributions. For example, [Et(3)NH](2)B(12)H(10)I-CONHpropyl, [(125)I]2b had high concentrations in kidney (1 h, 19.8%ID/g; 4 h, 26.5%ID/g), whereas [Et(3)NH](2)B(10)H(8)I-CONHpropyl, [(125)I]1e had much lower concentrations in kidney (1 h, 6.6%ID/g; 4 h, 0.27%ID/g). Interestingly, when another salt of the closo-decaborate(2-), [nBu(4)N](2)B(10)H(8)I-CONHpropyl, [(125)I]1b, was evaluated, the route of excretion appeared to be hepatobiliary rather than renal. Identical biotin derivatives containing the two closo-borate(2-) cage moieties had similar tissue distributions, except the closo-decaborate(2-) derivative had lower concentrations in kidney (1 h, 19.9%ID/g; 4 h, 24.4%ID/g vs 1 h, 38.9%ID/g; 4 h, 40.6%ID/g). In summary, the higher reactivity, faster tissue clearance, and lower kidney concentrations make the closo-decaborate(2-) more favorable for further studies using them in reactive groups for (211)At labeling of biomolecules.

Dataset Information

Primary Amine Nucleophilic Addition to Nitrilium Closo-Dodecaborate [B12H11NCCH3]-: A Simple and Effective Route to the New BNCT Drug Design.

Publications

Primary Amine Nucleophilic Addition to Nitrilium <i>Closo</i>-Dodecaborate [B<sub>12</sub>H<sub>11</sub>NCCH<sub>3</sub>]<sup>-</sup>: A Simple and Effective Route to the New BNCT Drug Design.

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