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Synthesis of Carboxyphosphonates and...

Matthiesen, Robert Armin.

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Synthesis of Carboxyphosphonates and Bisphosphonates as Potential GGTase II and GGDPS Inhibitors.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Synthesis of Carboxyphosphonates and Bisphosphonates as Potential GGTase II and GGDPS Inhibitors./
Author:	Matthiesen, Robert Armin.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
Description:	257 p.
Notes:	Source: Dissertation Abstracts International, Volume: 79-12(E), Section: B.
Contained By:	Dissertation Abstracts International79-12B(E).
Subject:	Organic chemistry. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10680882
ISBN:	9780438151444

Synthesis of Carboxyphosphonates and Bisphosphonates as Potential GGTase II and GGDPS Inhibitors.
Matthiesen, Robert Armin.

Synthesis of Carboxyphosphonates and Bisphosphonates as Potential GGTase II and GGDPS Inhibitors. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 257 p.

Source: Dissertation Abstracts International, Volume: 79-12(E), Section: B.

Thesis (Ph.D.)--The University of Iowa, 2018.

Inhibition of enzymes in the isoprenoid biosynthetic pathway (IBP) plays an important role in the treatment of bone diseases and lowering cholesterol. The IBP begins with the enzyme HMG-CoA reductase catalyzing the conversion of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonic acid. Mevalonic acid is then converted to isopentenyl pyrophosphate (IPP) via the intermediate mevalonate-5-diphosphate. Three molecules of IPP are joined by the enzyme farnesyl diphosphate synthase (FDPS), which yields the intermediate farnesyl pyrophosphate (FPP). FPP is an important substrate and represents the branch point in the pathway. Compounds which disrupt this pathway at FDPS include risedronate, lovastatin, and zoledronate. It is believed these compounds express their pharmacological effects on a further downstream enzyme.

ISBN: 9780438151444Subjects--Topical Terms:

523952
Organic chemistry.

Synthesis of Carboxyphosphonates and Bisphosphonates as Potential GGTase II and GGDPS Inhibitors.
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100 1 $a Matthiesen, Robert Armin. $3 3351322
245 1 0 $a Synthesis of Carboxyphosphonates and Bisphosphonates as Potential GGTase II and GGDPS Inhibitors.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2018
300 $a 257 p.
500 $a Source: Dissertation Abstracts International, Volume: 79-12(E), Section: B.
500 $a Adviser: David F. Wiemer.
502 $a Thesis (Ph.D.)--The University of Iowa, 2018.
520 $a Inhibition of enzymes in the isoprenoid biosynthetic pathway (IBP) plays an important role in the treatment of bone diseases and lowering cholesterol. The IBP begins with the enzyme HMG-CoA reductase catalyzing the conversion of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonic acid. Mevalonic acid is then converted to isopentenyl pyrophosphate (IPP) via the intermediate mevalonate-5-diphosphate. Three molecules of IPP are joined by the enzyme farnesyl diphosphate synthase (FDPS), which yields the intermediate farnesyl pyrophosphate (FPP). FPP is an important substrate and represents the branch point in the pathway. Compounds which disrupt this pathway at FDPS include risedronate, lovastatin, and zoledronate. It is believed these compounds express their pharmacological effects on a further downstream enzyme.
520 $a Further downstream from FDPS the IBP includes the key enzymes geranylgeranyl diphosphate synthase (GGDPS), which is responsible for the production of geranylgeranyl pyrophosphate (GGPP) and necessary for protein prenylation of the proteins Ras, Rho, and Rab. The second key enzyme is geranylgeranyl transferase II (GGTase II), which is responsible for the transfer of GGPP to Rab proteins. Rab proteins, which play an essential role for both protein secretion and trafficking, are of great interest as a therapeutic target for the bone disease multiple myeloma. Multiple myeloma is a disorder of malignant plasma cells, characterized by the overproduction of monoclonal protein, antibodies, or light chains, which can ultimately thicken the blood.
520 $a Targeting the prevention of geranylgeranylation of the Rab proteins by the enzyme GGTase II can happen through two different strategies. The first would be an indirect route, which would aim to inhibit the enzymes upstream from GGTase II. This could include the enzymes HMG-CoA reductase, FDPS, and GGDPS. Drugs that inhibit the earlier steps in the IBP indirectly prevent protein geranylgeranylation but they also limit formation of other key processes further downstream. The second approach would be a direct inhibition of the enzyme responsible for protein prenylation, GGTase II. There are very few know inhibitors of GGTase II. One such inhibitor is a carboxyphosphonate 3-PEHPC, a mimic of the bisphosphonate risedronate. Unfortunately, 3-PEHPC does not display an attractive potency.
520 $a Efforts to develop a more potent inhibitor of the enzyme GGTase II, have focused on the preparation of a family of carboxyphosphonates containing a triazole core, and these compounds were prepared via click chemistry. Their activity has been studied, but the salts that were successfully made were ultimately inactive in comparison to 3-PEHPC. Previous attempts at forming isoprene-containing triazole carboxyphosphonates, as isoprene chains were shown to help increase activity towards GGTase II, proved difficult and unsuccessful. Focus was then switched to alteration of isoprene bisphosphonate triazoles as GGDPS inhibitors in attempts to increase activity towards this enzyme. The biological activity of these bisphosphonates was found to be selective and potent inhibitors of GGDPS, with little to no activity towards the GGTase II enzyme.
520 $a In an effort to develop more potent inhibitors, isoprene triazole carboxyphosphonates were produced in an attempt to enhance the biological activity towards GGTase II. Along with forming a family of isoprene bisphosphonate compounds to increase the biological activity towards GGDPS in comparison to other previously made bisphosphonates. These carboxyphosphonate and bisphosphonate compounds were prepared through click chemistry and tested for their activity toward GGTase II and GGDPS.
590 $a School code: 0096.
650 4 $a Organic chemistry. $3 523952
650 4 $a Chemistry. $3 516420
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690 $a 0485
710 2 $a The University of Iowa. $b Chemistry. $3 1680584
773 0 $t Dissertation Abstracts International $g 79-12B(E).
790 $a 0096
791 $a Ph.D.
792 $a 2018
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10680882