Senolytic activity of piperlongumine analogues: Synthesis and biological evaluation

Abstract

Selective clearance of senescent cells (SCs) has emerged as a potential therapeutic approach for age-related diseases, as well as chemotherapy- and radiotherapy-induced adverse effects. Through a cell-based phenotypic screening approach, we recently identified piperlongumine (PL), a dietary natural product, as a novel senolytic agent, referring to small molecules that can selectively kill SCs over normal or non-senescent cells. In an effort to establish the structure-senolytic activity relationships of PL analogues, we performed a series of structural modifications on the trimethoxyphenyl and the α,β-unsaturated δ-valerolactam rings of PL. We show that modifications on the trimethoxyphenyl ring are well tolerated, while the Michael acceptor on the lactam ring is critical for the senolytic activity. Replacing the endocyclic C2-C3 olefin with an exocyclic methylene at C2 render PL analogues 47-49 with increased senolytic activity. These α-methylene containing analogues are also more potent than PL in inducing ROS production in WI-38 SCs. Similar to PL, 47-49 reduce the protein levels of oxidation resistance 1 (OXR1), an important oxidative stress response protein that regulates the expression of a variety of antioxidant enzymes, in cells. This study represents a useful starting point toward the discovery of senolytic agents for therapeutic uses.

Transient metabolic improvement in obese mice treated with navitoclax or dasatinib/quercetin

“…In turn, new compounds were discovered that selectively induced apoptosis in senescence cells, that were termed senolytics [16]. The description of the first senolytic treatments by the combination of dasatinib with quercetin in vitro [17], or the inhibitor of the Bcl-2 family of antiapoptotic proteins navitoclax [18], was followed by many other new, and still less studied senolytic compounds [19][20][21]. In general, senolytics have been used in mouse models to alleviate senescence-related diseases [16,[22][23][24] The use of senolytic compounds has been previously reported for the treatment of type 2 diabetes in mouse models.…”

Missing Link in the Homologous Series of Lactams: The X-ray Structure of Valerolactam

“…[15][16][17] Additionally, several bioactive compounds are valerolactam derivatives. [18][19][20][21][22] Only recently, the biotechnological production of valerolactam (1) 23 and a lactam biosensor 24 have been introduced. So far, the molecular structure of 1 has only been described in respective co-crystals [25][26][27][28][29][30][31] and metal complexes.…”

“…Valerolactam has been suggested as a system to mimic the base pairing in nucleic acids . Moreover, 1 is a valuable precursor for the total synthesis of different natural products − and is frequently employed in the development of chemical methodologies. − Additionally, several bioactive compounds are valerolactam derivatives. − Only recently, the biotechnological production of valerolactam ( 1 ) and a lactam biosensor have been introduced. So far, the molecular structure of 1 has been described in only respective cocrystals − and metal complexes. − Here, we describe for the first time a crystal structure of valerolactam ( 1 ) in the absence of other ligands, completing a homologous structural series of small- and medium-sized lactams.…”

The Jekyll and Hyde of Cellular Senescence in Cancer

“…Consistent with this knowledge, the inactivation of Akt signaling by an allosteric inhibitor, MK2206, can also trigger apoptosis in prostate cancer cells senesced by an androgen antagonist enzalutamide [199]. Piperlongumine, a natural extract with anti-tumor activities in non-small cell lung cancer (NSCLC), is a senolytic in various contexts [57,113,117,200,201]. Piperlongumine-induced senolysis is associated with increased ROS production via the degradation of antioxidant protein oxidation resistant 1 (OXR1) and the inhibition of the PI3K/Akt/mTOR pathway [202][203][204].…”