Original articleExploration of α-aminophosphonate N-derivatives as novel, potent and selective inhibitors of protein tyrosine phosphatases
Graphical abstract
Highlights
► New α-aminophosphonates are synthesized and characterized. ► PTP inhibition assays show 5 potently and selectively inhibits PTP1B and TCPTP. ► Compound 5 is cell permeable with lower cytotoxicity.
Introduction
Protein tyrosine phosphatases play an important role in catalyzing protein tyrosine dephosphorylation and modulating several cellular signal transduction pathways [1]. It is known that the dysregulation of PTPs activities could cause aberrant tyrosine phosporylation, which makes for the pathogenesis of several human diseases, such as cancers, autoimmune disorders, diabetes and obesity [2]. It has been demonstrated that PTP1B acts as a negative regulator of insulin and leptin-mediated processes [3]. TCPTP is crucial for inflammation control. TCPTP null mice develop progressive systemic inflammatory disease as shown by chronic myocarditis, gastritis, nephritis, and sialadenitis as well as elevated serum interferon-γ and tumor necrosis factor α in vivo [4]. Abnormal expression of many PTPs (SHP-2, PTP1B, TCPTP, PRL-3, CDC14, LMW-PTP, Cdc25, etc.) is found in various cancers [5]. Because of the role of PTPs in the disease onset and progression, PTP inhibitors especially that can selectively inhibit the particular PTP are therefore highly desirable as promising targeted therapeutic drugs [5](b), [6].
As mimics of natural amino acids, α-aminophosphonic acids and relative derivatives are currently attracting a great deal of interest in medicinal chemistry due to their important biological effects [7]. They are reported to have antibacterial activities [8], to act as inhibitors of enzymes such as rennin, HIV proteases, serine proteases and so on [9]. Some studies demonstrated that phosphorous compounds were effective PTP1B inhibitors [10]. Moreover, our recent research indicated that dinuclear copper complexes of α-aminophosphonate containing bisphenol can potently inhibit PTPs with some selectivity [11]. Therefore, α-aminophosphonate may also be developed as PTPs inhibitors.
From crystal structures of PTP1B [12], the active-site cysteine (Cys215) situated at the amino-terminus of α-4 is at the base of a cleft on the surface of the protein formed by residues of the PTP1B signature motif (residues from His214 to Arg222). The bell-mouthed cleft has a diameter in range of 10–18 Å. Thus, a sterical tetrahedral phosphonate, –PO(OR)2, is selected in order to block up the active-site. Based on this point, α-aminophosphonate N-derivatives, o-cresol–CH(–NHR)–PO(OR1)(OR2), are good candidates for our design: i) R = rigid group, R1 = R2 = ethyl; ii) R = rigid group, R1 = R2 = H; iii) R = flexible group, R1 = H, R2 = ethyl; iv) R = flexible side chains from proteinogenic amino acids, R1 = H, R2 = ethyl. For situations i) and ii), it can engender significant rigid effect and thus influence the structural assembly with an appropriate plug to decrease their contact between substrate and Cys215. In the light of this, we synthesized and characterized seventeen α-aminophosphonate compounds and investigated their inhibitory effect against PTPs.
Section snippets
Synthesis of o-cresol α-aminophosphonate N-derivatives
In the synthesis of aminophosphonic acids, Pudovik reaction as well as other pathways, like Mannich-type reaction and Kabachnik–Fields reaction are powerful and direct methods for construction of P–C–N bonds [13], [14], [15], [16], [17]. The Pudovik reaction involves the addition of the P–H bond of phosphonic acid esters to Schiff bases and forms an asymmetric center in α-position to the phosphorus atom if there are two different substituents in C-terminal. Expediently, the Kabachnik–Fields
Conclusions
A series of novel α-aminophosphonate N-derivatives are synthesized and characterized. The structures of compounds 1–4 are determined by X-ray crystal analysis. PTPs inhibition tests reveal that some of the α-aminophosphonate N-derivatives inhibit PTPs moderately while compound 5 is a potent and selective inhibitor of PTP1B and TCPTP. The substitute groups and their positions slightly influence the inhibitory effects. Kinetic analysis indicates that these compounds are competitive inhibitors of
General methods
All reagents and solvents were purchased commercially and used without further purification. Deionized water was used for all chemical experiments and double-distilled water was used to prepare buffer solutions as well as biological evaluation. pH values of buffer solutions were measured using a PHS-3TC pH meter. All reactions were magnetically stirred. Elemental analyses (EAs) were carried out with a VARI-EL elemental analyzer. IR spectra (4000–400 cm−1) were recorded using a Shimadzu Fourier
Acknowledgments
This work was supported financially by the National Natural Science Foundation of China (21001070 and 21171109), the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry (20093602), the Natural Science Foundation of Shanxi Province (2010011011-2, 2011011009-1 and 2011021006-2), Graduate Innovation Foundation of Shanxi Province of China and Instrumental Analysis Foundation of Large Scale Instruments of Shanxi University of China.
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