Background: Cancer is one of the leading causes of mortality globally. To cope with cancer, it is
necessary to develop anticancer drugs. Bioactive natural products, i.e. diarylheptanoids, have gained significant
attention of researchers owing to their intriguing structures and potent biological activities. In this article, considering
the development of anticancer drugs with enhanced selectivity towards cancerous cells, a series of
Cyclic Diarylheptanoids (CDHs) are designed, synthesized and evaluated their biological activity.
Objective: To establish an easy route for the synthesis of diarylheptanoids, and evaluate their antiproliferative,
and topoisomerase-I & -IIα inhibitory activities, for developing potential anticancer drugs among CDHs.
Methods: Diarylheptanoids were synthesized from reported linear diarylheptanoids using the classical Ullmann
reaction. Antibacterial activity was evaluated by the filter paper disc diffusion method. Cell viability was assessed
by measuring mitochondrial dehydrogenase activity with a Cell Counting Kit (CCK-8). Topoisomerases I
and II (topo-I and -IIα) inhibitory activity was measured by the assessment of relaxation of supercoiled pBR322
plasmid DNA. IFD protocol of Schrodinger Maestro v11.1 was used to characterize the binding pattern of
studied compounds with the ATPase domain of the human topo-IIα.
Results: The synthesized CDHs were evaluated for their biological activities (antibacterial, antiproliferative, and
topoisomerase-I & -IIα inhibitory activities, respectively). Leading to obtain a series of anticancer agents with
the least inhibitory activities against different microbes, improving their selectivity for cancer cells. In brief,
most of the synthesized CDHs had excellent antiproliferative activity against T47D (human breast cancer cell
line). Pterocarine possessed the strongest activity (2i; IC50 = 0.63μM) against T47D. The cyclic diarylheptanoid
2b induced 30% inhibition of topoisomerase-IIα activity at 100μM compared with the reference of etoposide,
which induced 72% inhibition. Among the tested compounds, galeon (2h) displayed very low activity against
four bacterial strains. Compounds 2b, 2h, and 2i formed hydrogen bonds with Thr215, Asn91, Asn120, Ala167,
Lys168 and Ile141 residues, which are important for binding of ligand compound to the ATPase binding site of
topoisomerase IIα by acting as ATP competitive molecule validated by docking study. In silico Absorption,
Distribution, Metabolism and Excretion (ADME) analysis revealed the predicted ADME parameters of the
studied compounds which showed recommended values.
Conclusion: A series of CDHs were synthesized and evaluated for their antibacterial, antiproliferative, and
topo-I & -IIα inhibitory activities. SARs study, molecular docking study and in silico ADME analysis were
conducted. Five compounds exhibited excellent and selective antiproliferative activity against the human breast
cancer cell line (T47D). Among them, a compound 2h showed topo-IIα activity by 30% at 100μM, which represented
a moderate intensity of inhibition compared with etoposide. Three of them formed hydrogen bonds with
Thr215, Asn91, Asn120, and Ala167 residues, which are considered as crucial residues for binding to the ATPase
domain of topoisomerase IIα. According to in silico drug-likeness property analysis, three compounds are
expected to show superiority over etoposide in case of absorption, distribution, metabolism and excretion.