Novel nonsecosteroidal VDR ligands with phenyl-pyrrolyl pentane skeleton for cancer therapy

Zhuang, G.; Hao, Meixi; Xu, Meng; Su, Zhigui; Kang, Zisheng; Xue, Lingjing; Zhang, Can

doi:10.1016/j.ejmech.2015.10.042

Cited by 10 publications

(8 citation statements)

References 21 publications

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“… However, compared with 1,25(OH) 2 D 3 , the binding affinity and transcriptional activity of LG190178 were modest. Therefore, to find more potential nonsecosteroidal VDR agonists, 225 nonsteroidal 1,25(OH) 2 D 3 analogues using LG190178 as the leading compound were designed, synthetized, and screened in our previous studies. − …”

Section: Resultsmentioning

confidence: 99%

“…In order to discover new VDR agonists without hypercalcemia, our group have designed and characterized a series of nonsecosteroidal VDR agonists that bear a phenyl-pyrrolyl pentane scaffold. − Among them, compounds 11b and 11d (Figure ) showed satisfactory binding affinity and transcriptional activation . However, the structure of these compounds can further be optimized for better activity and application in more refractory indications.…”

Section: Introductionmentioning

confidence: 99%

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Novel Nonsecosteroidal Vitamin D Receptor Modulator Combined with Gemcitabine Enhances Pancreatic Cancer Therapy through Remodeling of the Tumor Microenvironment

Kang

et al. 2020

J. Med. Chem.

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In a pancreatic tumor microenvironment, activated pancreatic stellate cells (PSCs) produce extracellular matrix (ECM) to form a barrier to drug penetration. Moreover, the interaction between cancer cells and activated PSCs promotes the tumor growth. Vitamin D receptor (VDR), as a key regulator to promote the recovery of PSCs to the resting state, is an attractive therapeutic target for pancreatic cancer. Herein, we reported the design and synthesis of 57 nonsecosteroidal VDR modulators based on the skeleton of phenyl-pyrrolyl pentane. Among them, compounds C4, I5, and I8 exhibited excellent VDR affinity and effective inhibition of the activation of PSCs, as well as potent suppression of the interaction between cancer cells and PSCs in vitro. In vivo, compound I5 combined with gemcitabine achieved efficacious antitumor activity without causing hypercalcemia. In conclusion, the compounds designed in our study can remodel the tumor microenvironment and are expected to be candidates for the treatment of pancreatic cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel Nonsecosteroidal Vitamin D Receptor Modulator Combined with Gemcitabine Enhances Pancreatic Cancer Therapy through Remodeling of the Tumor Microenvironment

Kang

et al. 2020

J. Med. Chem.

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“…Recently, a lot of attention has been drawn to nonsecosteroidal vitamin D mimics, − such as bisphenol derivative ( 4 ), tris-aromatic derivatives ( 5 ), and carborane derivatives ( 6 ), − due to their less calcium mobilization and simpler structures. Previously, we have reported phenyl-pyrrolyl pentane skeleton as a novel nonsecosteroidal VDR ligand skeleton, which possessed the potential to inhibit proliferation of cancer cells without inducing hypercalcemia effect. − However, we found that some compounds had no effect on cancer cells but show significant inhibitory effect on HSCs activation, indicating that VDR agonists may affect HSCs more strongly than cancer cells. Therefore, it is noteworthy to verify whether these nonsecosteroidal vitamin D ligands can act as effective as 1,25(OH) 2 D 3 or calcipotriol that with secosteroidal skeleton for preventing the progression of liver fibrosis but have smaller side effects like hypercalcemia.…”

Section: Introductionmentioning

confidence: 83%

Design, Synthesis, and Antifibrosis Activity in Liver of Nonsecosteroidal Vitamin D Receptor Agonists with Phenyl-pyrrolyl Pentane Skeleton

et al. 2018

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Liver fibrosis is characterized by excessive deposition of extracellular matrix (ECM) components and results in impaired liver function. Vitamin D plays a critical role in the development of liver fibrosis as it inhibits transforming growth factor β1 (TGFβ1)-induced excessive deposition of ECM in activated hepatic stellate cells (HSCs). Here, a series of novel nonsecosteroidal vitamin D receptor (VDR) agonists with phenyl-pyrrolyl pentane skeleton was designed and synthesized. Among them, seven compounds including 15a exhibited more efficient inhibitory activity in collagen deposition and fibrotic gene expression. Histological examination results displayed that compound 15a treatment prevented the development of hepatic fibrosis that induced by carbon tetrachloride (CCl4) injections in mice. In addition, compound 15a, unlike the positive control calcipotriol and 1,25(OH)2D3, did not cause hypercalcemia that is toxic to nerve, heart, and many other organs. These findings provide novel insights into drug discoveries for hepatic fibrosis using nonsecosteroidal VDR modulators.

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“…First, we retained the phenyl-pyrrolyl pentane skeleton, which was able to form strong hydrophobic interactions with the hydrophobic pocket of VDR. 32 Next, we introduced diethylcarbinol as the terminal hydrophobic group in the phenyl side chain to improve the biological activities, as similar modifications were reported in both secosteroidal and nonsteroidal vitamin D analogues. 27,33,34 A previous report showed that lexicalcitol (Figure 1A), which possessed a diethylcarbinol moiety in its side chain, was at least 100-fold more effective in terms of its biological activity than calcitriol.…”

Section: ■ Introductionmentioning

confidence: 89%

“…31 On the basis of that study, the pyrrolyl side chains were modified to improve the antiproliferative activity, and the results showed that the designed compounds exhibited promising antiproliferative activities in vitro. 32 In this study, to further improve the antiproliferative effects against cancer cells and the pharmacokinetic properties in vivo, 26 novel vitamin D analogues with phenyl-pyrrolyl pentane skeletons have been designed and synthesized, and their bioactivities have been evaluated in vitro and in vivo. First, we retained the phenyl-pyrrolyl pentane skeleton, which was able to form strong hydrophobic interactions with the hydrophobic pocket of VDR.…”

Section: ■ Introductionmentioning

confidence: 99%

Further Developments of the Phenyl-Pyrrolyl Pentane Series of Nonsteroidal Vitamin D Receptor Modulators as Anticancer Agents

et al. 2018

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The vitamin D receptor (VDR), which belongs to the nuclear-receptor superfamily, is a potential molecular target for anticancer-drug discovery. In this study, a series of nonsteroidal vitamin D mimics with phenyl-pyrrolyl pentane skeletons with therapeutic potentials in cancer treatment were synthesized. Among them, 11b and 11g were identified as the most effective agents in reducing the viability of four cancer-cell lines, particularly those of breast-cancer cells, with IC values in the submicromolar-concentration range. In addition, 11b and 11g possessed VDR-binding affinities and displayed significant partial VDR-agonistic activities determined by dual-luciferase-reporter assays and human-leukemia-cell-line (HL-60)-differentiation assays. Furthermore, 11b and 11g inhibited tumor growth in an orthotopic breast-tumor model via inhibition of cell proliferation and induction of cell apoptosis. More importantly, 11b and 11g exhibited favorable pharmacokinetic behavior in vivo and did not increase serum calcium levels or cause any other apparent side effects. In summary, 11b and 11g act as novel VDR modulators and may be promising candidates for cancer chemotherapy.

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Novel nonsecosteroidal VDR ligands with phenyl-pyrrolyl pentane skeleton for cancer therapy

Cited by 10 publications

References 21 publications

Novel Nonsecosteroidal Vitamin D Receptor Modulator Combined with Gemcitabine Enhances Pancreatic Cancer Therapy through Remodeling of the Tumor Microenvironment

Novel Nonsecosteroidal Vitamin D Receptor Modulator Combined with Gemcitabine Enhances Pancreatic Cancer Therapy through Remodeling of the Tumor Microenvironment

Design, Synthesis, and Antifibrosis Activity in Liver of Nonsecosteroidal Vitamin D Receptor Agonists with Phenyl-pyrrolyl Pentane Skeleton

Further Developments of the Phenyl-Pyrrolyl Pentane Series of Nonsteroidal Vitamin D Receptor Modulators as Anticancer Agents

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