OCT4/c-MYX axis as a mechanism of resistance to 13-cis retinoic acid in neuroblastoma

The Center for Innovative Drug Discovery (CIDD) will provide Dr. Min Kang at Texas Tech Health Science Center with medicinal chemistry support to perform custom synthesis and SAR study of narciclasine. as well as the derivatives of high-throughput screening hit Life Chemical E10 chemotype. The CIDD will provide all the necessary services. qualified personnel. materials. equipment and the facilities to ensure the requested tasks are completed. The requested tasks may include the following activities: developing synthesis methods. optimizing reaction conditions. and justifying the acquirable target compounds. The CIDD will aim to deliver 5-20 mg supplies of the proposed target compounds that are outlined in the scheme below. 
 As described in the scheme below. the proposed syntheses for narciclasine analogs are depicted in two medicinal chemistry strategies. Both total synthesis and natural product approaches will aim to prepare total of 40 to 60 analogs with specific SAR focuses on the substitution of aryl-A ring and functional group manipulation of C1. C2. N5 and C7 to improve the physical-chemical properties such as logD and tPSA. The proposed syntheses are primarily based on the independently reported work by Sarlah and Kiss groups. Additional steps and alternative routes will be amended accordingly in order to complete the target compounds for narciclasine chemotype.
 As described in the scheme below. for the Life Chemicals library hit. we will conduct a 3-points SAR study to aim to prepare total of 50 to 80 analogs. which could be rapidly assembled via a three-steps processes including (1) a SNAr or Buchwald-Hartwig amination coupling of various amines (green) with numerous amino-heteroaryl bromides (red). (2) deprotection of the amino group. and (3) acylation of the resulting amino-intermediates with series of ???.???-unsaturated acids or acyl chlorides (blue).
 The CIDD will perform all the requested tasks in attempt to complete the target compounds with purity >95%. The CIDD will include full analytical characterization (1H NMR. and HPLC/MS) of the final compounds along with a delivery sheet and supporting analytical data. The material synthesized by the CIDD will be done under non-GMP conditions and is not intended for human use.