RESUMO
Biosynthetically and chemically derived analogs of the antibiotic pactamycin and de-6-methylsalicylyl (MSA)-pactamycin have attracted recent interest as potential antiprotozoal and antitumor drugs. Here, we report a 3.1-Å crystal structure of de-6-MSA-pactamycin bound to its target site on the Thermus thermophilus 30S ribosomal subunit. Although de-6-MSA-pactamycin lacks the MSA moiety, it shares the same binding site as pactamycin and induces a displacement of nucleic acid template bound at the E-site of the 30S. The structure highlights unique interactions between this pactamycin analog and the ribosome, which paves the way for therapeutic development of related compounds.
Assuntos
Pactamicina/química , Pactamicina/metabolismo , Subunidades Ribossômicas Menores de Bactérias/química , Subunidades Ribossômicas Menores de Bactérias/metabolismo , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/metabolismo , Cristalografia por Raios X , Modelos Moleculares , Conformação Molecular , Pactamicina/análogos & derivados , Ligação Proteica , RNA Ribossômico 16S/química , RNA Ribossômico 16S/metabolismo , Thermus thermophilus/metabolismoRESUMO
A total of eight new analogs of pactamycin were prepared and tested alongside pactamycin and three of its natural congeners for antibacterial, anticancer, and antiprotozoal activities. The present study highlights the effects of changing the urea and aniline groups especially with regard to anticancer and antiprotozoal activities.
Assuntos
Antibacterianos/química , Antineoplásicos/química , Antiprotozoários/química , Pactamicina/análogos & derivados , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Antiprotozoários/farmacologia , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Linhagem Celular Tumoral , Humanos , Malária Falciparum/tratamento farmacológico , Neoplasias/tratamento farmacológico , Pactamicina/farmacologia , Plasmodium falciparum/efeitos dos fármacosRESUMO
This article describes synthetic studies that culminated in the first total synthesis of pactamycin and pactamycate and, in parallel, the two known congeners, de-6-MSA-pactamycin and de-6-MSA-pactamycate, lacking the 6-methylsalicylyl moiety. Starting with L-threonine as a chiron, a series of stereocontrolled condensations led to a key cyclopentenone harboring a spirocyclic oxazoline. A series of systematic functionalizations led initially to the incorrect cyclopentanone epoxide, which was "inverted" under solvolytic conditions. Installation of the remaining groups and manipulation of the oxazoline eventually led to pactamycin, pactamycate, and their desalicylyl analogues.