Synthesis of a Series of Acodazole and Naphthothiophene-Deuterioporphyrins and Metalloporphyrins

Sondhi, Sham M.; Magan, A.; Lown, J. William

doi:10.1246/bcsj.65.579

Cited by 9 publications

(5 citation statements)

References 6 publications

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“…11 The di-Nim-linked lysine 15 was prepared by initial Boc deprotection of 9 and subsequent coupling to 5 with HBTU (Scheme 2). The first route involved prior preparation of the di-Nim-linked lysine 15.…”

Section: Synthesismentioning

confidence: 99%

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Amino acid-linked porphyrin-nitroimidazole antibiotics targeting Porphyromonas gingivalis

et al. 2015

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The periodontal pathogen Porphyromonas gingivalis requires porphyrin supplementation for growth. Previously, in order to inhibit P. gingivalis growth, we synthesised very effective 'Trojan horse' ester and amide-linked deuterporphyrin-nitroimidazole (DPIX-Nim) adducts that exploited this requirement to transport metronidazole-derived antibiotics with excellent antimicrobial selectivity and recognition by the HA2 porphyrin binding site. Herein, in the context of developing topical agents to target P. gingivalis, l-amino acids are incorporated into adducts as linkers to improve uptake. Ten 13- and 17-propionic amide regioisomers of l-amino acid-linked deuterporphyrin-nitroimidazole adducts were synthesised using a peptide coupling approach. DPIX-Lys regioisomers without attached nitroimidazole were also synthesised as comparison compounds. All the porphyrin adducts bound (Kd50 7 to 20 nM) to a recombinant HA2 receptor with similar binding affinity to haem, except the lysine-proline linked DPIX-Lys(Boc)Pro-Nim adducts (Kd50 300 nM) and the DPIX-Lys(Nim)-Nim adducts (Kd50 200 nM), both of which have large appended groups. DPIX-Lys(Boc)-Nim, DPIX-Lys(OH)-Nim, and DPIX-Pro-Nim adducts were shown to be very effective against P. gingivalis. DPIX-Lys(Boc)Pro-Nim adducts and DPIX-Lys(Nim)-Nim adducts showed weak activity. Importantly, DPIX-Lys(Boc)-Nim adducts were selective for P. gingivalis and, unlike metronidazole, did not kill a range of other anaerobic bacteria isolated from the human gastrointestinal tract.

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Section: Synthesismentioning

confidence: 99%

“…Mtz-CO 2 H 5 was prepared from Mtz 3 in 32% yield following the literature. 11 The di-Nim-linked lysine 15 was prepared by initial Boc deprotection of 9 and subsequent coupling to 5 with HBTU (Scheme 2). Fmoc deprotection of 15 with DBU and coupling to the DPIX mono-methyl esters 10 gave adducts 16a and 16b in a 90% yield.…”

Section: Synthesismentioning

confidence: 99%

Amino acid-linked porphyrin-nitroimidazole antibiotics targeting Porphyromonas gingivalis

et al. 2015

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“…Esters 8 were prepared by the controlled hydrolysis of DPIX dimethyl ester with 4 M hydrochloric acid. 16 With this strategy it is possible to use an excess of met-NH 2 5. The yield of 9 and 10 for reaction of 8 with 5 was increased to 88%.…”

Section: Synthesismentioning

confidence: 99%

Porphyrin-linked nitroimidazole antibiotics targeting Porphyromonas gingivalis

et al. 2009

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Periodontal disease is an inflammatory process affecting supporting tissues surrounding the teeth. The anaerobic gram-negative bacterium Porphyromonas gingivalis is implicated in the disease. This organism requires the uptake of porphyrins most apparently as haem 1 from local haemorrhage and it has a HA2 receptor on the outer membrane for this purpose that provides the opportunity to achieve selective anti-microbial activity. Uniquely, this receptor is based on recognition of porphyrin macrocycle and on a propionic acid side-chain rather than recognition of the coordinated metal ion through chelation, a process used by other organisms with the HasA porphyrin receptor. Porphyrin-antibiotic conjugates 11, 12, 13a and 13b were designed as potential highly selective P. gingivalis inhibitors, a key point being that they are based on the use of free-base porphyrins to render them unpalatable to other organisms. These compounds were synthesised from metronidazole 4 and deuteroporphyrin IX 3. Conjugates 11, 12, 13a and 13b are all recognised by the HA2 receptor of P. gingivalis, bind as strongly as haem 1 to HA2 and are highly effective. For example, the amide-linked mono-metronidazole mono-acid adducts 11 and 12 have the same growth inhibitory activity towards P. gingivalis and both are two-fold more active than metronidazole 4 and ten- to twenty-fold more effective than the metronidazole derivative, amine 5. The methyl esters 9 and 10, in contrast, are not recognised by HA2 and are ineffective in inhibiting P. gingivalis, leading to the conclusion that capture by HA2 may be necessary for activity of the adducts. Preliminary growth inhibition assays involving a range of bacteria have demonstrated the high selectivity of conjugates 13a and 13b towards P. gingivalis.

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“…To increase the potency of tripyrrole polyamide or bisbenzimidazole-type molecules, numerous conjugates incorporating intercalating or alkylating moieties have been synthesized. 19 Our research group has pursued a complementary approach in developing a new class of agents we call microgonotropens (MGTs). 20 MGTs consist of a minor groove binding moiety functionalized with alkylamine side chains which are protonated and positively charged at neutral pH and capable of forming electrostatic bonds with the negatively charged phosphodiester backbone of DNA.…”

Section: Introductionmentioning

confidence: 99%

“…Our Approach. To increase the potency of tripyrrole polyamide or bisbenzimidazole-type molecules, numerous conjugates incorporating intercalating or alkylating moieties have been synthesized . Our research group has pursued a complementary approach in developing a new class of agents we call microgonotropens (MGTs) .…”

Section: Introductionmentioning

confidence: 99%

Recognition in the Minor Groove of Double-Stranded DNA by Microgonotropens

Satz

Bruice

2002

Acc. Chem. Res.

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Microgonotropens consist of a minor groove binding moiety functionalized with alkylamine side chains which are protonated and positively charged at neutral pH and capable of forming electrostatic bonds with the negatively charged phosphodiester backbone of DNA. We have investigated the interactions between microgonotropens and double-stranded DNA by a combination of fluorescence, ultraviolet, and nuclear magnetic resonance spectroscopy. Our work reveals why microgonotropens are such potent inhibitors of the binding of transcription factors to their DNA binding sites.

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Synthesis of a Series of Acodazole and Naphthothiophene-Deuterioporphyrins and Metalloporphyrins

Cited by 9 publications

References 6 publications

Amino acid-linked porphyrin-nitroimidazole antibiotics targeting Porphyromonas gingivalis

Amino acid-linked porphyrin-nitroimidazole antibiotics targeting Porphyromonas gingivalis

Porphyrin-linked nitroimidazole antibiotics targeting Porphyromonas gingivalis

Recognition in the Minor Groove of Double-Stranded DNA by Microgonotropens

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