Heasquinazolinone, a New Heat-Shock Metabolite Produced by Thermotolerant <i>Streptomyces</i> sp. HR41

We previously discovered metabolites that are either enhanced or specifically produced by actinomycetes in high-temperature cultures, which were designated as heat-shock metabolites (HSMs). In this study, we investigated HSMs produced by thermotolerant Streptomyces sp. HR41. HPLC-UV analysis revealed the presence of a peak, designated HSM (1), with maximum UV absorptions at 204, 246, and 282 nm, in ethyl acetate extract of Streptomyces sp. HR41. NMR and MS analyses indicated that the planar structure of 1 was 3,4-dihydro-4-methyl-2(1H)-quinazolinone. The chiral-phase HPLC analysis and comparison of the optical rotation value with that of related compounds were performed to examine the stereochemistry of 1 at C4. Thus, 1 was estimated to be an enantiomeric mixture of (S)- and (R)-3,4-dihydro-4-methyl-2(1H)-quinazolinone (1a and 1b), with an approximate enantiomer ratio of S/R = 18 : 82. This is the first discovery of 1 as a natural product, and it was therefore designated (S)- and (R)-heasquinazolinone. The biological activity of 1a and 1b was evaluated using several bioassay systems. The compounds selectively suppressed the growth of HT29 cells in 3-dimensional (3D) culture, with 50% inhibitory concentrations of 19 and 30 µM, respectively, indicating no apparent cytotoxicity in 2D culture.