Discovery of potent parthenolide-based antileukemic agents enabled by late-stage P450-mediated C-H functionalization
Kolev, JN; O'Dwyer, KM; Jordan, CT; Fasan, R
| HERO ID | 2900094 |
|---|---|
| In Press | No |
| Year | 2014 |
| Title | Discovery of potent parthenolide-based antileukemic agents enabled by late-stage P450-mediated C-H functionalization |
| Authors | Kolev, JN; O'Dwyer, KM; Jordan, CT; Fasan, R |
| Journal | ACS Chemical Biology |
| Volume | 9 |
| Issue | 1 |
| Page Numbers | 164-173 |
| Abstract | The sesquiterpene lactone parthenolide has recently attracted considerable attention owing to its promising antitumor properties, in particular in the context of stem-cell cancers including leukemia. Yet, the lack of viable synthetic routes for re-elaborating this complex natural product has represented a fundamental obstacle toward further optimization of its pharmacological properties. Here, we demonstrate how this challenge could be addressed via selective, late-stage sp(3) C-H bond functionalization mediated by P450 catalysts with tailored site-selectivity. Taking advantage of our recently introduced tools for high-throughput P450 fingerprinting and fingerprint-driven P450 reactivity prediction, we evolved P450 variants useful for carrying out the highly regioselective hydroxylation of two aliphatic sites (C9 and C14) in parthenolide carbocyclic backbone. By chemoenzymatic synthesis, a panel of novel C9- and C14-modified parthenolide analogs were generated in order to gain initial structure-activity insights on these previously inaccessible sites of the molecule. Notably, some of these compounds were found to possess significantly improved antileukemic potency against primary acute myeloid leukemia cells, while exhibiting low toxicity against normal mature and progenitor hematopoietic cells. By identifying two 'hot spots' for improving the anticancer properties of parthenolide, this study highlights the potential of P450-mediated C-H functionalization as an enabling, new strategy for the late-stage manipulation of bioactive natural product scaffolds. |
| Doi | 10.1021/cb400626w |
| Pmid | 24206617 |
| Is Certified Translation | No |
| Dupe Override | No |
| Is Public | Yes |
| Language Text | English |