Novel inhibitors of guanosine monophosphate synthetase as therapeutic agents

A compound, free technology, applied in the field of novel guanosine monophosphate synthase inhibitors, which can solve the problems of lack of effective and specificity, limited utilization, etc.

Pending Publication Date: 2021-07-30
UNIV OF SOUTHERN CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The lack of potent and specific GMPS inhibitors severely limits the utilization of GMPS as a target in therapeutic applications

Method used

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  • Novel inhibitors of guanosine monophosphate synthetase as therapeutic agents
  • Novel inhibitors of guanosine monophosphate synthetase as therapeutic agents
  • Novel inhibitors of guanosine monophosphate synthetase as therapeutic agents

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0097] Development of new monophosphate osteoside synthase inhibitors

[0098] Single phosphate chinelide enzyme (GMPS) is a dual-domain enzyme that produces ammonia, which is transferred to the synthetic domain to convert XMP to GMP (nucleotide precursor of RNA). . Therefore, and figure 1 The GMPS is shown to play an important role in cell division and proliferation and viral infection.

[0099] A series of new compounds have been developed in the lack of effective and specific GMPS inhibitors, and their ability to induce GMPS enzyme activity inhibition is developed.

[0100] like figure 2 The developed compounds shown have the structure as described in two brackets (I) and (II). In general structures (I) and (II), X is N or CH, R 1 Is (alkyl, acyl, alkoxy, halo, amino, amide, alkenyl, alkynyl), and R 2 It is (alkyl, acyl, alkoxy, halo, amino, amide, alkenyl, alkynyl).

[0101] like image 3 The pre-reporting conditions and modified composite structures (1-5) based on two bracket...

example 2

[0103] Evaluation of efficacy of GMPS inhibitor

[0104] By monitoring the UV absorbance at 290 nm and the five compounds were tested in the enzymatic determination by determining IC50, the efficacy of recombinant GMPs was tested. Summarized the IC obtained in Table 3 50 value. Three compounds (1, 2 and 4) in namolar IC 50 Value inhibits GMPS while discovering that the other two (3 and 5) is low. Structure - Activity Relationship (SAR) Indicates that the chloroacetamide group is essential for effective combination with GMPS.

[0105] Compound IC 50 (nm)

[0106] Table 3. Determination of compounds in recombinant human GMPS IC 50 value.

example 3

[0108] Assessment of covalent combination of compound 1 and GMPS in living cells

[0109] In order to assess the binding ability of GMPs in the alternating cell, the most effective inhibitor (i.e., compound 1) is evaluated covalently bonded to GMPs in the live cells.

[0110] HEK293 cells were treated with various concentrations for 20 minutes. Cells were washed with DPBS (dubelco phosphate buffer), centrifuged, and then cleaved using NP40-based buffer. The resulting cell lysate and TAMRA laminate subjected to Cu-catalyzed azide-alkyne ring addition reaction (CuAAc), and then analyzed by SDS PAGE and visualized TAMRA fluorescence. like Figure 4A The display is observed at approximately 75 kDa to a protruding strip that matches the size of the GMP. This result indicates that the compound 1 is covalently bonded to the GMPS, as the observed it is expected to be expected for the importance of the parental bond that binds to the target. Further, the dose reaction indicates that the co...

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PUM

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Abstract

The invention provides a series of GMPS enzyme inhibitors. The invention includes potent GMPS inhibitors that specifically and covalently bind to GMPS, exhibit broad anti-cancer activity, block the infection efficiency of viruses, and have the potentials to suppress undesired immune responses. These novel inhibitors of GMPS, and their derivatives, have tremendous potentials to be used as therapeutic agents for the treatment of cancers, viral infection and immune disorders.

Description

[0001] Cross-reference [0002] The priority interest of the US sequence number 62 / 730, 871, filed on September 13, 2018, according to 35U.s.c. §119 (e), which is incorporated herein by reference. Technical field [0003] The present invention generally relates to a monophosphate cycoside synthase inhibitor, and more particularly to the use of a new monophosphate synthase inhibitor for treating a disease or condition and is used as an immunosuppressive agent. [0004] governmental support [0005] The present invention is carried out in accordance with the funding CHE-1455306 granted under the National Science Foundation (National Science Foundation). The government has certain rights to the present invention. Background technique [0006] Single biosynthesis pathway involving monophosphate (IMP) first transforming into monophosphate 黄 黄 (IMP) and subsequent conversion to GMP conversion, the latter step by one enzyme-single phosphate Syndide enzyme (GMPS) catalyzed. GMPS is a du...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D239/94C07C235/56C07C237/42A61P35/00A61K31/167A61K31/517A61K45/06
Inventor 张超倪锋A·阿卡尼亚卡B·埃斯皮诺萨
Owner UNIV OF SOUTHERN CALIFORNIA
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