Synthesis of transition state inhibitors for N-riboside hydrolases and transferases

doi:10.1016/S0040-4020(96)01172-6

Tetrahedron

Volume 53, Issue 8, 24 February 1997, Pages 2915-2930

https://doi.org/10.1016/S0040-4020(96)01172-6 Get rights and content

Abstract

A number of 1,4-dideoxy-1,4-imino-1-(S)-(substituted phenyl)-d-ribitols bearing aromatic OH, NH₂, NO₂, CO₂H and halogeno moieties, and a 3-pyridyl analogue have been synthesized. The key step is the condensation of aryllithium or aryl Grignard reagents with the imine 3; derived from the protected 1,4-dideoxy-1,4-imino-d-ribitol 4.

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References (26)

D.J Hammond et al.
Mol. Biochem. Parasitol.
(1984)
V.C Dewey et al.
Arch. Biochem. Biophys.
(1973)
R.L Miller et al.
J. Biol. Chem.
(1984)
D.W Parkin et al.
J. Biol. Chem.
(1991)
B Estupinán et al.
J. Biol. Chem.
(1994)
D.W Parkin
J. Biol. Chem.
(1996)
B.A Horenstein et al.
Tetrahedron Lett.
(1993)
V.L Schramm et al.
J. Biol. Chem.
(1994)
Y Endo et al.
J. Biol. Chem.
(1987)
G.W.J Fleet et al.
Tetrahedron
(1988)

B.C Laguzza et al.

Tetrahedron Lett.

(1981)

K.S Webb et al.

Tetrahedron Lett.

(1995)

L.H Miller

Science

(1992)

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Transition state analogues of plasmodium falciparum and human orotate phosphoribosyltransferases
2013, Journal of Biological Chemistry
Citation Excerpt :
Inhibitor 16 was synthesized using methods previously described (46). The iminoribitol-, pyrrolidine-, and serinol-based inhibitors were synthesized by an extension of published methods for the synthesis of immucillin-H, 4′-deaza-1′-aza-2′-deoxy-1′-(9-methylene)-immucillin-H, and serinol-N-(9-methylene)-immucillin-H, respectively (see supplemental data) (40, 47–49). The identities of all inhibitors were confirmed by high-resolution mass spectrometry.
The survival and proliferation of Plasmodium falciparum parasites and human cancer cells require de novo pyrimidine synthesis to supply RNA and DNA precursors. Orotate phosphoribosyltransferase (OPRT) is an indispensible component in this metabolic pathway and is a target for antimalarials and antitumor drugs. P. falciparum (Pf) and Homo sapiens (Hs) OPRTs are characterized by highly dissociative transition states with ribocation character. On the basis of the geometrical and electrostatic features of the PfOPRT and HsOPRT transition states, analogues were designed, synthesized, and tested as inhibitors. Iminoribitol mimics of the ribocation transition state in linkage to pyrimidine mimics using methylene or ethylene linkers gave dissociation constants (K_d) as low as 80 nm. Inhibitors with pyrrolidine groups as ribocation mimics displayed slightly weaker binding affinities for OPRTs. Interestingly, p-nitrophenyl riboside 5′-phosphate bound to OPRTs with K_d values near 40 nm. Analogues designed with a C5-pyrimidine carbon–carbon bond to ribocation mimics gave K_d values in the range of 80–500 nm. Acyclic inhibitors with achiral serinol groups as the ribocation mimics also displayed nanomolar inhibition against OPRTs. In comparison with the nucleoside derivatives, inhibition constants of their corresponding 5′-phosphorylated transition state analogues are largely unchanged, an unusual property for a nucleotide-binding site. In silico docking of the best inhibitor into the HsOPRT active site supported an extensive hydrogen bond network associated with the tight binding affinity. These OPRT transition state analogues identify crucial components of potent inhibitors targeting OPRT enzymes. Despite their tight binding to the targets, the inhibitors did not kill cultured P. falciparum.
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Synthesis of transition state inhibitors for N-riboside hydrolases and transferases

Abstract

Mol. Biochem. Parasitol.

Arch. Biochem. Biophys.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Tetrahedron Lett.

J. Biol. Chem.

J. Biol. Chem.

Tetrahedron

Tetrahedron Lett.

Tetrahedron Lett.

Science