Determination of the importance of the stereochemistry of psorospermin in topoisomerase II–induced alkylation of DNA and in vitro and in vivo biological activity

Abstract

Psorospermin is a natural product that has been shown to have activity against drug-resistant leukemia lines and AIDS-related lymphoma. It has also been shown to alkylate DNA through an epoxide-mediated electrophilic attack, and this alkylation is greatly enhanced at specific sites by topoisomerase II. In this article, we describe the synthesis of the two diastereomers of O 5 -methyl psorospermin and their in vitro activity against a range of solid and hematopoietic tumors. The diastereomeric pair (F)-(2VR,3VR) having the naturally occurring enantiomer (2VR,3VR) is the most active across all the cell lines and shows approximately equal activity in both drug-sensitive and drug-resistant cell lines. In subsequent studies using all four enantiomers of O 5 -methyl psorospermin, the order of biological potency is (2VR,3VR) > (2VR,3VS) = (2VS,3VR) > (2VS,3VS). This order of potency is also found in the topoisomerase IIinduced alkylation of O 5 -methyl psorospermin and can be rationalized by molecular modeling of the psorospermin-duplex binding complex. Therefore, this study defines the optimum stereochemical requirements for both the topoisomerase II -induced alkylation of DNA and the biological activity by psorospermin and its O 5 -methyl derivatives. Finally, (2VR,3VR) psorospermin was found to be as effective as gemcitabine in slowing tumor growth in vivo in a MiaPaCa pancreatic cancer model. In addition, (2VR,3VR) psorospermin in combination with gemcitabine was found to show an at least additive effect in slowing tumor growth of MiaPaCa.

Experimental and computational thermochemical studies of 9-R-xanthene derivatives (ROH, COOH, CONH2)

“…The xanthene moiety is a substructure of several organic compounds that have shown to have marked and desirable physiological activity, and it appears also to be an important building block for the synthesis of new pharmacological active compounds [1][2][3][4][5][6]. Some xanthene derivatives are also important dyes like fluorescein, eosin and rhodamine.…”

Psorospermin structural requirements for P-glycoprotein resistance reversal

“…In comparison, in the same pair of cell lines, doxorubicin showed a 500-fold level of resistance (17). These data indicate that psorospermin is either not a substrate for P-gp or perhaps a modulator of it.…”

“…Previous studies have determined that, in the 8226/D40 cell line, the IC 50 of psorospermin ranges from 0.037 μM (PS-RR) to 0.335 μM (PS-SS) (17). Due to this variability of cytotoxic potency, we determined if stereochemistry was a factor in its resistance-reversal activity.…”

“…Although studied for over thirty years, the four isomers of psorospermin were only recently synthesized in 2005 (Figure 1A) (14). Significantly, psorospermin has activity against drug-resistant cell lines, including breast cancer, leukemias, and AIDS-related lymphomas (15–17). Psorospermin's cytotoxic activity stems from its ability to intercalate with DNA at the major groove by site-directed electrophilic addition, resulting in a covalent psorospermin–DNA adduct (Figure 1B) (18).…”

“…Because psorospermin's cytotoxic activity is not affected by overexpression of P-gp or other ABC transport proteins (17), psorospermin may play a role in MDR modulation. In this study, we investigate the mechanism underlying psorospermin's P-gp modulation activity in multiple myeloma cells.…”