Adenosine and 2′‐Deoxyadenosine Modified with Boron Cluster Pharmacophores as New Classes of Human Blood Platelet Function Modulators

Abstract

Novel types of adenosine and 2'-deoxyadenosine derivatives containing boron clusters at positions C2', N6, or C8 were synthesized. The effect of these modified compounds on platelet function was studied. Modification of adenosine at the C2' position with a para-carborane cluster (C(2)B(10)H(11)) results in efficient inhibition of platelet function, including aggregation, protein secretion, and P-selectin expression induced by thrombin or ADP. These preliminary findings and the new chemistry proposed form the basis for the development of a new class of adenosine analogues that modulate human blood platelet activities.

Synthesis and Biological Evaluation of Diaryl‐Substituted Carboranes as Inhibitors of Hypoxia Inducible Factor (HIF)‐1 Transcriptional Activity

“…[27,28] We have studied boron-based drug design. [34][35][36][37][38][39][40][41][42][43] For instance, we recently identified heat shock protein 60 (Hsp 60) as a primary target of ortho-carboranylphenoxyacetanilide, [40][41][42] an HIF-1a inhibitor, and determined that Hsp 60 plays an important role in the stabilization of HIF-1a under hypoxia; ortho-carborane function is essential for inhibition of Hsp 60 chaperone activity. [33] In particular, carboranes (icosahedral dicarba-closo-dodecaboranes; C 2 B 10 H 12 ) possess remarkable thermal and catabolic stability, and their icosahedral geometry and exceptional hydrophobicity have been used as hydrophobic pharmacophores in biologically active molecules interacting with their target proteins.…”

“…[33] In particular, carboranes (icosahedral dicarba-closo-dodecaboranes; C 2 B 10 H 12 ) possess remarkable thermal and catabolic stability, and their icosahedral geometry and exceptional hydrophobicity have been used as hydrophobic pharmacophores in biologically active molecules interacting with their target proteins. [34][35][36][37][38][39][40][41][42][43] For instance, we recently identified heat shock protein 60 (Hsp 60) as a primary target of ortho-carboranylphenoxyacetanilide, [40][41][42] an HIF-1a inhibitor, and determined that Hsp 60 plays an important role in the stabilization of HIF-1a under hypoxia; ortho-carborane function is essential for inhibition of Hsp 60 chaperone activity. [43] We focused on the tetrahydrofuran scaffold in manassantin A and designed compounds 1 and 2, which contain icosahedral 1,2-dicarba-closo-dodecaborane (ortho-carborane) and 1,7-dicarba-closo-dodecaborane (meta-carborane) frameworks as alternate scaffolds to that of manassantin A, as shown in Figure 1.…”

In Silico Carborane Docking to Proteins and Potential Drug Targets

“…In addition, carboranes and carborane derivatives have been found to be effective inhibitors of HIV-1 protease, 34À36 inducers of 20S proteasome activity, 37 and modulators of human blood platelet function. 38 In an effort to expand the medicinal chemistry of carboranes, we have attempted to identify further biological targets for which they might prove beneficial. In this systematic computational work, we lay the ground for an approach that is able to account for the interactions between a carborane molecule and proteins.…”

A convenient approach towards boron cluster modifications with adenosine and 2′-deoxyadenosine

“…Boron-containing nucleosides were originally designed as potential boron carriers for the boron neutron capture therapy (BNCT) of tumours [1]. Recently several other applications of nucleosideeboron cluster conjugates have been proposed, including RedOx-labels [2], IR-labels [3], modulators of the purinergic receptors activity or inhibitors of the blood platelets aggregation [4]. Thus, in last three decades a range of boronated nucleosides bearing boronic acids residue as well as boron clusters have been synthesized and tested [5,6].…”

“…Deoxyadenosine, modified with cobalt-bis(dicarbollide) (III) was prepared by the cleavage reaction of 1 by activated 6-NH 2 -group of protected deoxyadenosine [10]. The same approach was used for the preparation of the first modification of adenosine with undecaborate anion (IV) [4]. Finally, the coupling reaction of 2-ethynylpara-carborane and 8-bromo-deoxyadenosine resulted in a new derivative (V), where the boron cluster and a nucleoside were linked through the C-8 position of the 2 0 -deoxyadenosine [4].…”