Amides of (2Z,4E)-5-[(5,6-dichloroindol-2-yl)]-2-methoxy-N-[3-[4-(3-(carboxymethoxy)phenyl)] piperazin-1-yl]propyl-2,4-pentadienamide (1) and of 5-(5,6-dichloro-2-indolyl)-2-methoxy-2,4-pentadienoic acid (2) are strong inhibitors of the vacuolar ATPase located on the plasma membrane of osteoclasts. In order to understand which V-ATPase subunit is involved in the interaction with these novel inhibitors, analogs contg. a photoactivable group and an iodine atom were designed. A series of alcs. or amines contg. the photoactivable trifluoroaziridinophenyl or benzophenone moiety and an iodine atom were linked to the above acids via an ester or amide group. These compds. could be thereafter used as a radioactive photoprobe to label the protein. Whereas the compds. contg. the photoactivable groups maintained good inhibitory activity, the introduction of the bulky iodine atom was generally detrimental, decreasing potency significantly. Better results were obtained by linking 3-(4-aminopiperidinomethyl)-3'-iodobenzophenone to 3-ethoxy-4-(2-(5,6-dichlorobenzimidazolyl))benzoic acid to give the corresponding amide 27, that inhibited vacuolar ATP-ase with a IC50=140 nM. The feasibility of introducing a radioactive 125I atom was ascertained by exchanging the iodine with a tributylstannyl group, that was again substituted by iodine.

Synthesis of photoactivable inhibitors of osteoclast vacuolar ATPase / B. Biasotti, S. Dallavalle, L. Merlini, C. Farina, S. Gagliardi, C. Parini, P. Belfiore. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 11:10(2003 May 15), pp. 2247-2254.

Synthesis of photoactivable inhibitors of osteoclast vacuolar ATPase

S. Dallavalle
Secondo
;
L. Merlini;
2003

Abstract

Amides of (2Z,4E)-5-[(5,6-dichloroindol-2-yl)]-2-methoxy-N-[3-[4-(3-(carboxymethoxy)phenyl)] piperazin-1-yl]propyl-2,4-pentadienamide (1) and of 5-(5,6-dichloro-2-indolyl)-2-methoxy-2,4-pentadienoic acid (2) are strong inhibitors of the vacuolar ATPase located on the plasma membrane of osteoclasts. In order to understand which V-ATPase subunit is involved in the interaction with these novel inhibitors, analogs contg. a photoactivable group and an iodine atom were designed. A series of alcs. or amines contg. the photoactivable trifluoroaziridinophenyl or benzophenone moiety and an iodine atom were linked to the above acids via an ester or amide group. These compds. could be thereafter used as a radioactive photoprobe to label the protein. Whereas the compds. contg. the photoactivable groups maintained good inhibitory activity, the introduction of the bulky iodine atom was generally detrimental, decreasing potency significantly. Better results were obtained by linking 3-(4-aminopiperidinomethyl)-3'-iodobenzophenone to 3-ethoxy-4-(2-(5,6-dichlorobenzimidazolyl))benzoic acid to give the corresponding amide 27, that inhibited vacuolar ATP-ase with a IC50=140 nM. The feasibility of introducing a radioactive 125I atom was ascertained by exchanging the iodine with a tributylstannyl group, that was again substituted by iodine.
synthesis ; vacuolar ATP ; osteoclast ; photoactivable group
Settore CHIM/06 - Chimica Organica
Article (author)
File in questo prodotto:
Non ci sono file associati a questo prodotto.
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/8793
Citazioni
  • ???jsp.display-item.citation.pmc??? 3
  • Scopus 27
  • ???jsp.display-item.citation.isi??? 27
social impact