| Summary: | Withanolides constitute one of the most interesting classes of natural products due to their diversity of structures and biological activities. Our recent studies on withanolides obtained from plants of Solanaceae including <i>Withania somnifera</i> and a number of <i>Physalis</i> species grown under environmentally controlled aeroponic conditions suggested that this technique is a convenient, reproducible, and superior method for their production and structural diversification. Investigation of aeroponically grown <i>Physalis coztomatl</i> afforded 29 withanolides compared to a total of 13 obtained previously from the wild-crafted plant and included 12 new withanolides, physacoztolides I−M (<b>9</b>–<b>13</b>), 15<i>α</i>-acetoxy-28-hydroxyphysachenolide C (<b>14</b>), 28-oxophysachenolide C (<b>15</b>), and 28-hydroxyphysachenolide C (<b>16</b>), 5<i>α</i>-chloro-6<i>β</i>-hydroxy-5,6-dihydrophysachenolide D (<b>17</b>), 15<i>α</i>-acetoxy-5<i>α</i>-chloro-6β-hydroxy-5,6-dihydrophysachenolide D (<b>18</b>), 28-hydroxy-5<i>α</i>-chloro-6<i>β</i>-hydroxy-5,6-dihydrophysachenolide D (<b>19</b>), physachenolide A-5-methyl ether (<b>20</b>), and 17 known withanolides <b>3</b>–<b>5</b>, <b>8</b>, and <b>21</b>–<b>33</b>. The structures of <b>9</b>–<b>20</b> were elucidated by the analysis of their spectroscopic data and the known withanolides <b>3</b>–<b>5</b>, <b>8</b>, and <b>21</b>–<b>33</b> were identified by comparison of their spectroscopic data with those reported. Evaluation against a panel of prostate cancer (LNCaP, VCaP, DU-145, and PC-3) and renal carcinoma (ACHN) cell lines, and normal human foreskin fibroblast (WI-38) cells revealed that <b>8, 13</b>, <b>15</b>, and <b>17</b>–<b>19</b> had potent and selective activity for prostate cancer cell lines. Facile conversion of the 5,6-chlorohydrin <b>17</b> to its 5,6-epoxide <b>8</b> in cell culture medium used for the bioassay suggested that the cytotoxic activities observed for <b>17</b>–<b>19</b> may be due to in situ formation of their corresponding 5β,6β-epoxides, <b>8</b>, <b>27</b>, and <b>28</b>.
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