2. Academic Validation
  3. New camptothecin derivatives for generalized oncological chemotherapy: Synthesis, stereochemistry and biology

New camptothecin derivatives for generalized oncological chemotherapy: Synthesis, stereochemistry and biology

  • Bioorg Med Chem Lett. 2021 Aug 15:46:128146. doi: 10.1016/j.bmcl.2021.128146.
Beata Naumczuk 1,  Marcin Górecki 2,  Katarzyna Wiktorska 3,  Magdalena Urbanowicz 3,  Jerzy Sitkowski 4,  Katarzyna Lubelska 3,  Małgorzata Milczarek 3,  Elżbieta Bednarek 3,  Wojciech Bocian 3,  Lech Kozerski 4
Affiliations

Affiliations

  • 1 National Medicines Institute, Chełmska 30/34, 00-725 Warsaw, Poland; Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 42/52, 01-224 Warsaw, Poland. Electronic address: b.naumczuk@nil.gov.pl.
  • 2 Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 42/52, 01-224 Warsaw, Poland.
  • 3 National Medicines Institute, Chełmska 30/34, 00-725 Warsaw, Poland.
  • 4 National Medicines Institute, Chełmska 30/34, 00-725 Warsaw, Poland; Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 42/52, 01-224 Warsaw, Poland.
PMID: 34048881 DOI: 10.1016/j.bmcl.2021.128146
Abstract

Derivatives of SN38 were synthesized that were either monosubstituted at C-5 or C-9 or disubstituted at both C-5 and C-9. Substitution to C-5 led to the generation of pairs of diastereomers (2c-2 h) in a one-pot reaction and was readily separable by HPLC. The absolute configurations of C-5 were established by electronic circular dichroism experiments. Compounds were tested in vitro against human Cancer cell lines as well as a normal cell line. The impact of compounds 2a-2j on Cancer cells is significant and the IC50 values against the normal cell line are several times higher than that of SN38. Using the Mannich reaction we obtained a new innovative group of derivatives with unique biological properties that preserves the high cytotoxicity in Cancer cells and eliminates the acute toxicity to non-neoplastic cells, which can be considered a breakthrough in chemotherapy with the use of Topoisomerase I inhibitors from the camptothecin family.

Keywords

Biological activity; ECD spectroscopy; SN38 derivatives; Synthesis.

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