Polypharmacology of conformationally locked methanocarba nucleosides

Abstract

A single molecular scaffold can be adapted to interact with diverse targets, either separately or simultaneously. Nucleosides and nucleotides in which ribose is substituted with bicyclo[3.1.0]hexane are an example of a versatile drug-like scaffold for increasing selectivity at their classical targets: kinases, polymerases, adenosine and P2 receptors. Also, by applying structure-based functional group manipulations, rigidified adenosine derivatives can be repurposed to satisfy pharmacophoric requirements of various GPCRs, ion channels, enzymes and transporters, initially detected as off-target activities. Recent examples include 5HT2B serotonin receptor antagonists and novel dopamine transporter allosteric modulators. This directable target diversity establishes rigid nucleosides as privileged scaffolds.

The Role of the Phosphorus Atom in Drug Design

“…Since the first synthesis of conformationally locked carbanucleosides built on the rigid bicyclo[3.1.0]hexane system, a large number of rigid carbocyclic nucleosides and nucleotides built on this inflexible system have been described, exhibiting a wide range of pharmacological actions. These include adenosine deaminase, HIV reverse transcriptase, DNA (cytosine‐C5) methyl transferase, and several purine receptors . In addition, N ‐methano‐ carba ‐T ( 170 ) and S ‐methano‐ carba ‐T ( 171 ) represent a clarifying example of an unambiguous conformational preference for enzyme–drug interaction, with the conclusion that only the Northern conformer is responsible for potent activity against both herpes simplex viruses 1 and 2 (Figure ) …”

“…Phosphorus‐containing molecules, particularly nucleotide derivatives, are also relevant drugs in the purine field . Naturally occurring extracellular nucleosides and nucleotides bind and activate cell‐surface receptors, which are involved in an extensive signaling system .…”

“…2‐Methythioadenosine 5′‐diphosphate ( 172 ), widely used in pharmacological studies, is an agonist at three receptor subtypes: P2Y 1 , P2Y 12 , and P2Y 13 . Interestingly, the conformationally rigid counterpart built in a [3.1.0]hexane system 175 is a very potent and selective agonist at P2Y 1 R . Compound 176 is a Southern conformationally rigid analogue of UDP, the native agonist of P2Y 6 R. In this case, 176 was found to be more potent than UDP, whereas the corresponding Northern analogue was inactive .…”

“…Interestingly, the conformationally rigid counterpart built in a [3.1.0]hexane system 175 is a very potent and selective agonist at P2Y 1 R . Compound 176 is a Southern conformationally rigid analogue of UDP, the native agonist of P2Y 6 R. In this case, 176 was found to be more potent than UDP, whereas the corresponding Northern analogue was inactive . Compound 178 is a selective and competitive antagonist of P2Y 1 R. The conformationally rigid carbocyclic nucleotides 179 (2‐chloro‐ N 6 ‐methyl‐( N )‐methanocarba‐2′‐deoxyadenosine‐3′,5′‐bisphosphate; MR2279) and 180 (2‐iodo‐ N 6 ‐methyl‐( N )‐methanocarba‐2′‐deoxyadenosine‐3′,5′‐bisphosphate; MRS2500) are selective high‐affinity P2Y 1 receptor antagonists and are even more effective than their parent drug 178 .…”

“…These include adenosine deaminase, [161] HIV reverse transcriptase, [162] DNA (cytosine-C5) methyl transferase, [157] and several purine receptors. [163,164] In addition, N-methano-carba-T (170)a nd S-methano-carba-T (171)r epresent ac larifyinge xample of an unambiguousc onformational preference for enzyme-drug interaction,w ith the conclusion that only the Northern conformer [165] is responsible for potent activity against both herpes simplex viruses 1a nd 2 ( Figure 26). [158] Phosphorus-containing molecules, particularly nucleotide derivatives, are also relevant drugs in the purinef ield.…”