Three cyclic diarylheptanoids, myricanol (1), myricanone (2), and porson (3), were isolated from Myrica javanica (Myricaceae). As a major component, myricanol (1) was obtained from dry powdered bark and twigs (up to 1.6%). Transformation of myricanol (1) afforded 5-prenylmyricanol (4) and 5-benzylmyricanol (5) in 84.5% and 65% yields, respectively. The bioactivities of the isolated cyclic diarylheptanoids and their derivatives were investigated to determine their cytotoxicity and DPPH (2,2-diphenyl-1-picrylhydrazyl) scavenging activities. The cytotoxicity assay against murine leukaemia P-388 cells demonstrated that compounds 4 and 5 showed an almost two-fold increase in the activity of their parent molecule (1), with an IC50 value of 12 µM. Furthermore, the free radical scavenging assay showed that myricanol (1) had the highest radical scavenging activity, revealing the importance of the free phenolic group (IC50 39.3 µM).

Diarylheptanoids are secondary metabolites of plants that comprise a C6-C7-C6 scaffold. They can be broadly classified into linear-type and cyclic-type diarylheptanoids based on their chemical structures. Actinorhizal trees, such as Casuarina, Alnus, and Myrica, which form nodule symbiosis with actinomycetes Frankia, produce cyclic diarylheptanoids (CDHs); in Alnus sieboldiana Matsum. in particular, we have reported that the addition of CDHs leads to an increase in the number of nodules. However, the information available on the biosynthesis of CDHs is scarce. A greater number of plants CDHs (including those isolated from actinorhizal trees) with a saturated heptane chain have been isolated compared with linear, non-cyclic diarylheptanoids. To identify the genes involved in the synthesis of these compounds, genes with significant sequence similarity to existing plant double-bond reductases were screened in A. sieboldiana. This report describes the isolation and characterization of two A. sieboldiana double-bond reductases (AsDBR1 and AsDBR2) that catalyze the NADPH-dependent reduction of bisdemethoxycurcumin and curcumin. The optimum pH for the two enzymes was 5.0. The apparent Km values for bisdemethoxycurcumin and NADPH were 4.24 and 3.53 μM in the case of AsDBR1, and 2.55 and 2.13 μM for AsDBR2. The kcat value was 9.4-fold higher for AsDBR1 vs. AsDBR2 when using the bisdemethoxycurcumin substrate. Interestingly, the two AsDBRs failed to reduce the phenylpropanoid monomer.

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.
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.
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.
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.
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.