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Syntheses of Potent and Selective MMP-13 Inhibitors with Increased Metabolic Stability.

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	Syntheses of Potent and Selective MMP-13 Inhibitors with Increased Metabolic Stability./
Author:	Klu, Michael Worlako.
Description:	1 online resource (403 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 85-02, Section: B.
Contained By:	Dissertations Abstracts International85-02B.
Subject:	Infections. -
Online resource:	click for full text (PQDT)
ISBN:	9798380120395

Syntheses of Potent and Selective MMP-13 Inhibitors with Increased Metabolic Stability.
Klu, Michael Worlako.

Syntheses of Potent and Selective MMP-13 Inhibitors with Increased Metabolic Stability. - 1 online resource (403 pages)

Source: Dissertations Abstracts International, Volume: 85-02, Section: B.

Thesis (Ph.D.)--Universitaet Hamburg (Germany), 2023.

Includes bibliographical references

MMP-13 inhibitors: A dysregulation of matrix metalloproteinase (MMP)-13 has been correlated with pathophysiological conditions like human carcinomas, rheumatoid arthritis, and osteoarthritis. This makes MMP-13 a suitable target for drug development. Since the family of MMPs comprises more than 23 different members in humans, a potential drug candidate should selectively and potently inhibit MMP-13 in order to avoid side effects resulting from a lack of selectivity. Additionally, the desired drug candidate should have a suitable pharmacokinetic profile. To realize the aim of developing potent and selective inhibitors of MMP-13 that are metabolically more stable, the chemical structure of lead compound 41, a potent and selective picomolar inhibitor of MMP-13 from an earlier work of KALININ et al., was extensively varied to access structurally diverse inhibitors. First, to avoid a possible O-dealkylation, the oxymethylene moiety of the lipophilic side chain of 41 was replaced with ethylene, vinylene, and acetylene moieties. These varied lipophilic side chains were accessed from starting materials like 1,4-diiodobenzene (43), 1-bromo-4-iodobenzene (80), and 4-iodoaniline (49) by employing reactions like C-C couplings, catalytic hydrogenation, semi-reduction of alkynes, diazotization, and desilylation. The respective fluorinated derivatives were obtained by reacting the various hydroxylated side chains with DAST. Starting from hydroxyproline derivative 57, amide 59, the central building block of the synthesis, was obtained by benzoylation, MITSUNOBU, and saponification reactions. Thus, hydroxamic acids I were obtained after SONOGASHIRA coupling reactions of the various side chains with aryl iodide 59 and aminolyses with hydroxylamine. In order to replace the carbonyl function of 41 with a sulfonyl moiety, which is more stable to hydrolysis, proline derivative 57 was transformed into diastereomeric sulfonamides II via sulfonylation, MITSUNOBU, and saponification reactions. Hence, sulfonamide-based hydroxamic acids 72 and 73 were afforded by C-C couplings with ether-based terminal alkyne 71 and aminolyses.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798380120395Subjects--Topical Terms:

882242
Infections.
Index Terms--Genre/Form:

554714
Electronic books.

Syntheses of Potent and Selective MMP-13 Inhibitors with Increased Metabolic Stability.
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245 1 0 $a Syntheses of Potent and Selective MMP-13 Inhibitors with Increased Metabolic Stability.
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502 $a Thesis (Ph.D.)--Universitaet Hamburg (Germany), 2023.
504 $a Includes bibliographical references
520 $a MMP-13 inhibitors: A dysregulation of matrix metalloproteinase (MMP)-13 has been correlated with pathophysiological conditions like human carcinomas, rheumatoid arthritis, and osteoarthritis. This makes MMP-13 a suitable target for drug development. Since the family of MMPs comprises more than 23 different members in humans, a potential drug candidate should selectively and potently inhibit MMP-13 in order to avoid side effects resulting from a lack of selectivity. Additionally, the desired drug candidate should have a suitable pharmacokinetic profile. To realize the aim of developing potent and selective inhibitors of MMP-13 that are metabolically more stable, the chemical structure of lead compound 41, a potent and selective picomolar inhibitor of MMP-13 from an earlier work of KALININ et al., was extensively varied to access structurally diverse inhibitors. First, to avoid a possible O-dealkylation, the oxymethylene moiety of the lipophilic side chain of 41 was replaced with ethylene, vinylene, and acetylene moieties. These varied lipophilic side chains were accessed from starting materials like 1,4-diiodobenzene (43), 1-bromo-4-iodobenzene (80), and 4-iodoaniline (49) by employing reactions like C-C couplings, catalytic hydrogenation, semi-reduction of alkynes, diazotization, and desilylation. The respective fluorinated derivatives were obtained by reacting the various hydroxylated side chains with DAST. Starting from hydroxyproline derivative 57, amide 59, the central building block of the synthesis, was obtained by benzoylation, MITSUNOBU, and saponification reactions. Thus, hydroxamic acids I were obtained after SONOGASHIRA coupling reactions of the various side chains with aryl iodide 59 and aminolyses with hydroxylamine. In order to replace the carbonyl function of 41 with a sulfonyl moiety, which is more stable to hydrolysis, proline derivative 57 was transformed into diastereomeric sulfonamides II via sulfonylation, MITSUNOBU, and saponification reactions. Hence, sulfonamide-based hydroxamic acids 72 and 73 were afforded by C-C couplings with ether-based terminal alkyne 71 and aminolyses.
533 $a Electronic reproduction. $b Ann Arbor, Mich. : $c ProQuest, $d 2024
538 $a Mode of access: World Wide Web
650 4 $a Infections. $3 882242
650 4 $a Cancer. $3 581034
650 4 $a Physiology. $3 673386
650 4 $a Chemical elements. $3 565229
650 4 $a Disease. $3 568889
650 4 $a Rheumatoid arthritis. $3 645622
650 4 $a Biosynthesis. $3 674536
650 4 $a Bacteria. $3 600016
650 4 $a Amino acids. $3 1066910
650 4 $a Metabolism. $3 581368
650 4 $a Chromatography. $3 783938
650 4 $a Gram-negative bacteria. $3 883892
650 4 $a Bioavailability. $3 778473
650 4 $a Mass spectrometry. $3 583253
650 4 $a Bacterial infections. $3 1465450
650 4 $a Biochemistry. $3 582831
650 4 $a Organic chemistry. $3 1148722
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