Abstract
Conformationally restrained polyamine analog PG11047 is a well-known drug candidate that modulates polyamine metabolism and inhibits cancer cell growth in a broad spectrum of cancers. Here, we report a structure–activity relationship study of the PG11047 analogs (HPGs) containing alkyl chains of varying length, while keeping the unsaturated spermine backbone unchanged. Synthesis of higher symmetrical homologues was achieved through a synthetic route with fewer steps than the previous route to PG11047. The amphiphilic HPG analogs underwent self-assembly and formed spherically shaped nanoparticles whose size increased with the hydrophobic alkyl group’s increasing chain length. Assessment of the in vitro anticancer activity showed more than an eight-fold increase in the cancer cell inhibition activity of the analogs with longer alkyl chains compared to PG11047 in human colon cancer cell line HCT116, and a more than ten-fold increase in human lung cancer cell line A549. Evaluation of the inhibition of spermine oxidase (SMOX) showed no activity for PG11047, but activity was observed for its higher symmetrical homologues. Comparison with a reference SMOX inhibitor MDL72527 showed nine-fold better activity for the best performing HPG analog.
Original language | English |
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Article number | 2441 |
Journal | Molecules |
Volume | 27 |
Issue number | 8 |
DOIs | |
State | Published - 1 Apr 2022 |
Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
Funding
This work was supported by NIH grants R01, CA235863, CA204345, and the SWCRF Collaboration for a Cure Grant. The authors acknowledge the Nuclear Magnetic Resonance (NMR) facility from Eppley Institute for Research in Cancer and Allied Diseases and the Electron Microscopy Core Facility at the University of Nebraska Medical Center.
Funders | Funder number |
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Eppley Institute for Research in Cancer and Allied Diseases | |
SWCRF Collaboration | |
National Institutes of Health | R01, CA204345 |
National Cancer Institute | R01CA235863 |
University of Nebraska Medical Center |
Keywords
- PG11047
- cancer therapy
- polyamine analogs
- self-assembly
- spermine oxidase