(3-Amino-2-oxoalkyl)phosphonic acids and their analogs as novel inhibitors of D-alanine:D-alanine ligase

Chakravarty, Prasun K.; Greenlee, William J.; Parsons, William H.; Patchett, Arthur A.; Combs, Patricia L.; Roth, Alan; Busch, R.D.; Mellin, T.N.

doi:10.1021/jm00128a033

Cited by 98 publications

(68 citation statements)

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“…The cancer cell inhibition activity of the potentially dual functioning anticancer agent 16 was notable (Table 1), as was the broad spectrum antimicrobial action of amide 14. The latter substance (14) also inhibited the growth of the pathogenic fungus Cryptococcus neoformans (MIC = 64 µg/ml), the pathogenic bacterium Neisseria gonorrhoeae ATCC 49226 (MIC = 16 µg/ml), and the opportunistic bacteria Streptococcus pneumoniae ATCC 6303 (MIC = 8-16 µg/ml) and Enterococcus faecalis ATCC 29212 (MIC = 32-64 µg/ml). Prodrug 3a inhibited N. gonorrhoeae (MIC = 0.125 µg/ml) and E. faecalis (MIC = 16 µg/ml), and prodrug 6 inhibited N. gonorrhoeae (MIC = 4 µg/ml).…”

Section: Resultsmentioning

confidence: 99%

Antineoplastic Agents. 515. Synthesis of Human Cancer Cell Growth Inhibitors Derived from 3,4-Methylenedioxy-5,4‘-dimethoxy-3‘-amino-Z-stilbene

et al. 2005

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Further structure-activity relationship (SAR) exploration of 3,4-methylenedioxy-5,4′-dimethoxy-3′-amino-Z-stilbene (1a) derivatives resulted in the efficient synthesis of tyrosine amide hydrochloride 9, two tyrosine amide phosphate prodrugs (3a and 6), and sodium aspartate amide 11. Two additional cancer cell growth inhibitors (14 and 16) were synthesized by employing peptide coupling between amine 1a and the Dap residue of dolastatin 10 (4a) to yield amide 14 followed by to yield peptide 16. The latter represents a combination of stilbene 1a with the des-Doe tetrapeptide unit of the powerful tubulin assembly inhibitor dolastatin 10. Peptide 16 was examined for potential binding to tubulin in the vinca and/or colchicine regions and found to perform primarily as a relative of dolastatin 10. Amide 14 had anticryptococcal and antibacterial activities.We recently completed syntheses of 3'-amino derivatives (1a-b, 1d-j) of combretastatin A-2 (2c) 1 , encouraged by the remarkable success of the potent cancer vascular targeting [2][3][4] that occurs with combretastatin A-4 phosphate prodrug (CA4P) 2h. [5][6][7][8][9][10] Subsequently, we undertook the synthesis and initial anticancer evaluation of two phosphate derivatives (3a,b) of tyrosine stilbene amide 1i. Attachment of the phosphate group at the 3'-phenol position has been investigated in detail in the combretastatin A and B series. 1,[11][12][13] In the present study we chose to use the 4"-hydroxyl group of tyrosine amide 1i for attachment of a phosphate group (3a) as well as obtaining a diphosphoryl derivative (3b) by phosphorylating tyrosine amide 1i at both the amine 14 and hydroxyl groups. A parallel important objective of this research involved employing a tetrapeptide segment of dolastatin 10 (4a) for bonding to the 3′-amino group (1b). Dolastatin 10 (D-10, 4a), isolated 15-17 from the Indian Ocean sea hare Dolabella auricularia, has continued to progress through preclinical 18 and clinical development as an impressive antineoplastic agent. [19][20][21][22] Dolastatin 10 (4a) and various synthetic derivatives also have specific antifungal activity against Cryptococcus neoformans. 23,24 Previous SAR studies have confirmed that D-10 (4a) inhibits microtubule assembly by binding to the β-tubulin subunit near the vinca site. SAR studies have shown the des-Doe tetrapeptide unit (4b, Dov-Val-Dil-Dap) to be necessary for potent anticancer * To whom correspondence should be addressed. bpettit@asu 25,26 We now also report synthesis of the amide representing coupling of amine 1a to Dov-Val-Dil-Dap (4b). Results and DiscussionOur synthesis of the tyrosine stilbene amide 1i 27 presented the opportunity to develop two additional phosphate prodrugs in the combretastatin series. Accordingly, the 4"-phenol and α-amino groups were phosphorylated in one step using dibenzyl phosphite (1i to 5) (Scheme 1). Debenzylation of the resulting phosphate diesters (5) was achieved using bromotrimethylsilane to afford the free acid (3b) which was subsequently converted to sod...

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Section: Resultsmentioning

confidence: 99%

Antineoplastic Agents. 515. Synthesis of Human Cancer Cell Growth Inhibitors Derived from 3,4-Methylenedioxy-5,4‘-dimethoxy-3‘-amino-Z-stilbene

et al. 2005

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“…33 This aldehyde was then reacted with freshly in situ prepared Bestmann-Ohira reagent (dimethyl diazo-2-oxopropylphosphonate), 36 and the resulting intermediate alkyne 26 was readily deprotected in iodotrimethylsilane to generate 5 (Scheme 2). 37 Likewise, the synthesis of alkyne 6 started with aldehyde 27 (Boc-Ala-CHO 38 ) and reaction with the Bestmann-Ohira reagent to generate 28 (Scheme 2). After deprotecting the Boc this intermediate was coupled with BocThrĲtBu)-OH followed by another deprotection to facilitate alkyne 6.…”

Section: Design and Synthesismentioning

confidence: 99%

Design and synthesis of triazole-based peptidomimetics of a PSD-95 PDZ domain inhibitor

2016

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“…The acetylsulfanylethylketone (19) that differed from intermediate (12) by the distance between the carbonyl and mercapto groups, was prepared via the a,b-unsaturated compound (18). 20) Thus the aminoaldehyde (14) was transformed into the vinyl alcohol (17), which on Swern oxidation gave the corresponding a,b-unsaturated ketone (18). Compound 19 was obtained by an 1,4-addition of thioacetic acid to 18.…”

Section: -10mentioning

confidence: 99%

Design and Synthesis of Sulfur Based Inhibitors of Matrix Metalloproteinase-1.

Fujisawa

Odake

Ogawa

et al. 2002

CHEMICAL & PHARMACEUTICAL BULLETIN

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Fibroblast collagenase (MMP-1), a member of the matrix metalloproteinases family, is believed to be a pathogenesis of arthritis, by cleaving triple-helical type II collagen in cartilage. From the similarity of the active site zinc binding mode with hydroxamate, we designed and synthesized a a-mercaptocarbonyl possessing compounds (3-5), which incorporated various peptide sequences as enzyme recognition sites. The P 4 -P 1 peptide incorporating compound (3) exhibited as potent inhibition as the hydroxamate (1) and the carboxylate (2) type inhibitors, with an IC 50 of 10 ؊6 M order against MMP-1. But the inhibitor (3) related compounds (6-8) displayed decreased or no inhibitory potencies. These results suggest that the existence of both the carbonyl and thiol groups might be critical for the inhibition, and the distance between the two functional groups is important for inhibitory potency. For P n peptide incorporating compounds (4a-k), except for 4h and 4k, all compounds showed IC 50 values under sub-nanomolar. Among them, for potent inhibition, Leu was better than Phe and Val as the P 1 amino acid, and the P 2 position amino acid was necessary, and preferentially Phe. Insertion of the P n peptide into 4d or 4k, giving compounds 5a-c, did not increase the activities of 4d and 4k. Substitution of the mercapto group with other functional groups lost the activity of compound 4a. The stereochemical preference at the thiol-attached position was also determined by preparation of both isomers of 4a. It was found that the S configuration compound (36b) is approximately 100 times more potent than the corresponding R-isomer (36a).Key words matrix metalloproteinase; inhibitor; a-mercaptocarbonyl; isoserine; in vitro activity Design The X-ray crystal structures of MMP-1 with bound inhibitors reveal that the hydroxamate acts as a bidentate ligand with each oxygen at an optimal distance (2.1-2.2 Å) from the active-site zinc ion (structure A, Fig. 2). 13)From this structural analysis data, we reasoned that the amercaptocarbonyl group (structure B) at the cleavage site would chelate at the active-site zinc ion by both carbonyl and mercapto groups in a similar manner as the hydroxamate (Fig. 2). In comparison with the hydroxamate possessing MMPs inhibitors, little is known about thiol group including compounds. But, previously Donald and colleagues developed a b-mercapto carbonyl group possessing compound that exhibited 10 Ϫ7 M order of IC 50 against MMP-1.14) The compound differs in the distance between the carbonyl and mercapto groups from the structure B. In addition, Baxter and colleagues have prepared the thiol containing inhibitors utilizing computer-aided drug design, expecting new interactions with MMP-8 by hydrogen bonds, e.g. Ser172 of MMP-8.15) These compounds exhibited potent inhibitions with an IC 50 of 10 Ϫ7 -10 Ϫ9 M against MMP-3, -8, -9, but were not tested on MMP-1. We designed three different compounds containing an a-mercaptocarbonyl group, based on the enzyme recognition sites. The P 4 -P 1 peptide incorporati...

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(3-Amino-2-oxoalkyl)phosphonic acids and their analogs as novel inhibitors of D-alanine:D-alanine ligase

Cited by 98 publications

References 0 publications

Antineoplastic Agents. 515. Synthesis of Human Cancer Cell Growth Inhibitors Derived from 3,4-Methylenedioxy-5,4‘-dimethoxy-3‘-amino-Z-stilbene

Antineoplastic Agents. 515. Synthesis of Human Cancer Cell Growth Inhibitors Derived from 3,4-Methylenedioxy-5,4‘-dimethoxy-3‘-amino-Z-stilbene

Design and synthesis of triazole-based peptidomimetics of a PSD-95 PDZ domain inhibitor

Design and Synthesis of Sulfur Based Inhibitors of Matrix Metalloproteinase-1.

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