Total Synthesis of Homoseongomycin Enantiomers and Evaluation of Their Optical Rotation.

A total synthesis of each homoseongomycin enantiomer was accomplished in 17 total steps (longest linear sequence = 12 steps) and 10 chromatographic purifications. Several schemes were attempted to forge the key 5-membered ring, but only a Suzuki coupling-intramolecular Friedel-Crafts acylation sequence proved viable. Challenges encountered during the optical rotation characterization of the natural product left us with two important takeaways. First, highly colored compounds like homoseongomycin that absorb near/at the sodium d-line may require optical rotation measurements at other wavelengths. Second, high dilution of such compounds to obtain measurement at the sodium d-line could result in artificially large and incorrectly assigned specific rotations. To verify the optical rotation, electronic circular dichroism spectra were acquired for both homoseongomycin enantiomers and were transformed into optical rotary dispersions via the Kramers-Kronig transform. We note the wavelength dependency on rotation, and at the sodium d-line 589 nm, we reassign the optical rotation of L-homoseongomycin from (-) to (+).

Novel PDGFRB rearrangement in multifocal infantile myofibromatosis is tumorigenic and sensitive to imatinib.

Infantile myofibromatosis (IM) is an aggressive neoplasm composed of myofibroblast-like cells in children. Although typically localized, it can also present as multifocal disease, which represents a challenge for effective treatment. IM has previously been linked to activating somatic and germline point mutations in the PDGFRß tyrosine kinase encoded by the PDGFRB gene. Clinical panel-based targeted tumor sequencing of a tumor from a newborn with multifocal IM revealed a novel PDGFRB rearrangement, which was reported as being of unclear significance. Additional sequencing of cDNA from tumor and germline DNA confirmed a complex somatic/mosaic PDGFRB rearrangement with an apparent partial tandem duplication disrupting the juxtamembrane domain. Ectopic expression of cDNA encoding the mutant form of PDGFRB markedly enhanced cell proliferation of mouse embryo fibroblasts (MEFs) compared to wild-type PDGFRB and conferred tumor-forming capacity on nontumorigenic 10T1/2 fibroblasts. The mutated protein enhanced MAPK activation and retained sensitivity to the PDGFRß inhibitor imatinib. Our findings reveal a new mechanism by which PDGFRB can be activated in IM, suggest that therapy with tyrosine kinase inhibitors including imatinib may be beneficial, and raise the possibility that this receptor tyrosine kinase might be altered in a similar fashion in additional cases that would similarly present annotation challenges in clinical DNA sequencing analysis pipelines.