Synthesis and SAR investigation of biphenylaminoquinoline derivatives with benzyloxy substituents as promising anticancer agents.

The biphenyl scaffold represents a prominent privileged structure within the realms of organic chemistry and drug development. Biphenyl derivatives have demonstrated notable biological activities, including antimicrobial, anti-inflammatory, anti-HIV, and the treatment of neuropathic pain. Importantly, their anticancer abilities should not be underestimated. In this context, the present study involves the design and synthesis of a series of biphenyl derivatives featuring an additional privileged structure, namely the quinoline core. We have also diversified the substituents attached to the benzyloxy group at either the meta or para position of the biphenyl ring categorized into two distinct groups: [4,3']biphenylaminoquinoline-substituted and [3,3']biphenylaminoquinoline-substituted compounds. We embarked on an assessment of the cytotoxic activities of these derivatives in colorectal cancer cell line SW480 and prostate cancer cell line DU145 for exploring the structure-activity relationship. Furthermore, we determined the IC50 values of selected compounds that exhibited superior inhibitory effects on cell viability against SW480, DU145 cells, as well as MDA-MB-231 and MiaPaCa-2 cells. Notably, [3,3']biphenylaminoquinoline derivative 7j displayed the most potent cytotoxicity against these four cancer cell lines, SW480, DU145, MDA-MB-231, and MiaPaCa-2, with IC50 values of 1.05 µM, 0.98 µM, 0.38 µM, and 0.17 µM, respectively. This highly promising outcome underscores the potential of [3,3']biphenylaminoquinoline 7j for further investigation as a prospective anticancer agent in future research endeavors.

Discovery of the tryptanthrin-derived indoloquinazoline as an anti-breast cancer agent via ERK/JNK activation.

Tryptanthrin, an alkaloid applied in traditional Chinese medicine, exhibits a variety of pharmacological activities. This study aimed to investigate the anti-tumor activity of the tryptanthrin derivative (8-cyanoindolo[2,1-b]quinazoline-6,12-dione [CIQ]) in breast cancer cells. In both MDA-MB-231 and MCF-7 breast cancer cells, CIQ inhibited cell viability and promoted caspase-dependent apoptosis. At the concentration- and time-dependent ways, CIQ increased the levels of p-ERK, p-JNK, and p-p38 in breast cancer cells. We found that exposure to the JNK inhibitor or the ERK inhibitor partially reversed CIQ's viability. We also observed that CIQ increased reactive oxygen species (ROS) generation, and upregulated the phosphorylation and expression of H2AX. However, the pretreatment of the antioxidants did not protect the cells against CIQ's effects on cell viability and apoptosis, which suggested that ROS does not play a major role in the mechanism of action of CIQ. In addition, CIQ inhibited the invasion of MDA-MB-231 cells and decreased the expression of the prometastatic factors (MMP-2 and Snail). These findings demonstrated that the possibility of this compound to show promise in playing an important role against breast cancer.

Development of triazole-based PKC-inhibitors to overcome resistance to EGFR inhibitors in EGFR-mutant lung cancers.

Protein kinase C delta (PKCδ) is prominently expressed in the nuclei of EGFR-mutant lung cancer cells, and its presence correlates with poor survival of the patients undergoing EGFR inhibitor treatment. The inhibition of PKCδ has emerged as a viable approach to overcoming resistance to EGFR inhibitors. However, clinical-grade PKCδ inhibitors are not available, highlighting the urgent needs for the development of effective drugs that target PKCδ. In this study, we designed and synthesized a series of inhibitors based on the chemical structure of a pan PKC inhibitor sotrastaurin. This was achieved by incorporating a triazole ring group into the original sotrastaurin configuration. Our findings revealed that the sotrastaurin derivative CMU-0101 exhibited an elevated affinity for binding to the ATP-binding site of PKCδ and effectively suppressed nuclear PKCδ in resistant cells in comparison to sotrastaurin. Furthermore, we demonstrated that CMU-0101 synergistically enhanced EGFR TKI gefitinib sensitivity in resistant cells. Altogether, our study provides a promising strategy for designing and synthesizing PKCδ inhibitors with improved efficacy, and suggests CMU-0101 as a potential lead compound to inhibit PKCδ and overcome TKI resistance in lung cancers.

Novel 4-aminoquinoline analogs targeting the HIF-1α signaling pathway.

Background: The aminoquinoline core exhibits versatile pharmacological properties, particularly in the area of anticancer activity. This study was designed to investigate the potential of the 4-aminoquinoline scaffold in the development of anticancer agents by targeting the HIF-1α signaling pathway. Methodology: The authors synthesized multiple derivatives of 4-aminoquinoline containing heterocyclic rings by a microwave reactor and assessed the cytotoxicity and inhibitory effects of these derivatives on the HIF-1α signaling pathway. Conclusion: Compound 3s was identified as the most promising HIF-1α inhibitor due to its exceptional antiproliferative effects, with IC50 values of 0.6 and 53.3 nM observed in MiaPaCa-2 and MDA-MB-231 cells, respectively. Furthermore, compound 3s was found to inhibit HIF-1α expression by decreasing the level of HIF-1α mRNA.

Development of NS2B-NS3 protease inhibitor that impairs Zika virus replication.

Zika virus (ZIKV) is a mosquito-borne flavivirus that causes severe neurological disorders, such as microcephaly in fetuses. Most recently, an outbreak of ZIKV started in Brazil in 2015. To date, no therapeutic agents have been approved to treat ZIKV infection in the clinic. Here, we screened a small molecule inhibitor that can inhibit the function of ZIKV non-structural protein 2B (NS2B)-NS3 protease (ZIKV NS2B-NS3 protease), thereby interfering with viral replication and spread. First, we identified the half maximal inhibitory concentration (IC50) of compound 3 (14.01 µM), 8 (6.85 µM), and 9 (14.2 µM) and confirmed that they are all non-competitive inhibitors. In addition, we have used the blind molecular docking method to simulate the inhibition area of three non-competitive inhibitors (compound 3, 8, and 9) with the ZIKV NS2B-NS3 protease. The results indicated that the four allosteric binding residues (Gln139, Trp148, Leu150, and Val220) could form hydrogen bonds or non-bonding interactions most frequently with the three compounds. The interaction might induce the reaction center conformation change of NS2B-NS3 protease to reduce catalyzed efficiency. The concentration of compounds required to reduce cell viability by 50% (CC50), and the concentration of compounds required to inhibit virus-induced cytopathic effect by 50% (EC50) of three potential compounds are >200 µM, 2.15 µM (compound 3), > 200 µM, 0.52 µM (compound 8) and 61.48 µM, 3.52 µM (compound 9), and Temoporfin are 61.05 µM, 2 µM, respectively. To select candidate compounds for further animal experiments, we analyzed the selectivity index (SI) of compound 3 (93.02), 8 (384.61), 9 (17.46), and Temoporfin (30.53, FDA-approved drug against cancer). Compound 8 has the highest SI value. Therefore, compound 8 was selected for verification in animal models. In vivo, compound 8 significantly delayed ZIKV-induced lethality and illness symptoms and decreased ZIKV-induced weight loss in a ZIKV-infected suckling mouse model. We conclude that compound 8 is worth further investigation for use as a potential future therapeutic agent against ZIKV infection.

Synthesis and evaluation of biarylquinoline derivatives as novel HIF-1α inhibitors.

Hypoxia-inducible factor (HIF)-1α is a key transcription factor that contributes to aggressive and drug-resistant phenotypes in tumor cells under hypoxic conditions. Therefore, targeting HIF-1α represents a promising therapeutic strategy for cancer drug development. In the present study, we designed, synthesized, and evaluated a new series of biarylquinoline derivatives as potential HIF-1α inhibitors based on structure-activity relationship. Among these derivatives, compound 7f represents the optimal agent with IC50 values of 28 nM and 15 nM in suppressing the viability of MiaPaCa-2 and MDA-MB-231 cells, respectively. Compound 7f also exhibited potent efficacy in inhibiting hypoxia-induced migration of MDA-MB-231 and MiaPaCa-2 cells. Mechanistically, compound 7f suppressed HIF-1α expression by blocking transcription and protein translation, in lieu of facilitating protein degradation. Moreover, this HIF-1α downregulation was associated with compound 7f's ability to concomitantly inhibit multiple signaling pathways governing HIF-1 α expression at different levels, including those mediated by STAT3, MEK/ERK MAPK, and mTOR/4E-BP1. Together, these findings underscore the translational potential of these biarylquinoline derivatives to be developed as novel HIF-1α inhibitors, which warrants further investigations.

Synthetic Tryptanthrin Derivatives Induce Cell Cycle Arrest and Apoptosis via Akt and MAPKs in Human Hepatocellular Carcinoma Cells.

Trytanthrin, found in Ban-Lan-Gen, is a natural product containing an indoloquinazoline moiety and has been shown to possess anti-inflammatory and anti-viral activities. Chronic inflammation and hepatitis B are known to be associated with the progression of hepatocellular carcinoma (HCC). In this study, a series of tryptanthrin derivatives were synthesized to generate potent anti-tumor agents against HCC. This effort yielded two compounds, A1 and A6, that exhibited multi-fold higher cytotoxicity in HCC cells than the parent compound. Flow cytometric analysis demonstrated that A1 and A6 caused S-phase arrest and downregulated the expression of cyclin A1, B1, CDK2, and p-CDC2. In addition to inducing caspase-dependent apoptosis, A1 and A6 exhibited similar regulation of the phosphorylation or expression of multiple signaling targets, including Akt, NF-κB, and mitogen-activated protein kinases. The anti-tumor activities of A1 and A6 were also attributable to the generation of reactive oxygen species, accompanied by an increase in p-p53 levels. Therefore, A1 and A6 have potential clinical applications since they target diverse aspects of cancer cell growth in HCC.

Novel HIF-1α inhibitor CDMP-TQZ for cancer therapy.

Aim: Tumor cells adapt to hypoxic microenvironments by releasing the key transcription factor HIF-1α, which promotes angiogenesis, glycolytic phenotype, metastasis and erythropoiesis, allowing proliferation amid low oxygen levels. Therefore, therapeutic targeting of HIF-1α represents a viable strategy for cancer therapy. Methods & Results: The authors synthesized a series of novel tetrahydroquinazoline derivatives in six steps and demonstrated that their development had a unique ability to suppress HIF-1α expression through proteasomal degradation. Conclusion: Among these compounds, CDMP-TQZ (8bf) exhibited the highest antiproliferative potency in human cancer cells, in part through downregulation of HIF-1α.

Development of Novel Rhodacyanine-Based Heat Shock Protein 70 Inhibitors.

BACKGROUND: A growing body of evidence suggests that Hsp70, which is overexpressed in human breast tumors, plays a role in tumorigenesis and tumor progression in breast cancer as well as in its aggressive phenotypes. Hsp70 constitutes a potential therapeutic target in the treatment of this disease. METHODS: We developed a new series of rhodacyanine-based Hsp70 inhibitors, represented by compounds 1 and 6, in which the cationic pyridin-1-ium or thiazol-3-ium ring of existing Hsp70 inhibitors (e.g., JG-40 and JG-98) was replaced by a corresponding benzo- fused N-heterocycle. RESULTS: Several lines of evidence suggest that these benzo-fused derivatives may exert their antitumor activities, in part, by targeting Hsp70. These putative inhibitors displayed differential antiproliferative efficacy against breast cancer cells (IC50 as low as 0.25 µM) versus nontumorigenic MCF-10A breast epithelial cells (IC50 ≥ 5 µM). This was correlated with the corresponding Hsp70 expression levels. Using a protein refolding assay, we confirmed that these agents effectively inhibited the chaperone activity of Hsp70. Moreover, these inhibitors effectively suppressed the expression of well-known oncogenic client proteins of Hsp70's, including FoxM1, HuR, and Akt, which paralleled their antiproliferative efficacy. Supporting the established role of Hsp70 in regulating protein refolding, these derivatives induced autophagy, as manifested by the conversion of LC3B-I to LC3B-II. Notably, these putative Hsp70 inhibitors did not cause a compensatory elevation in Hsp90 expression, contrasting with the previously reported effects of Hsp90 inhibitors on Hsp70 upregulation. CONCLUSION: Together with the finding that compounds 1 and 6 showed improved microsomal stability, these results suggest the translational potential of these putative Hsp70 inhibitors to foster new strategies for cancer therapy. However, whether these benzo-fused rhodacyanines act on kinases or other targets remains unclear. It is currently under investigation.

Synthesis and biological evaluation of thiophenylbenzofuran derivatives as potential P-glycoprotein inhibitors.

P-Glycoprotein (P-gp) overexpression is a major mechanism by which cancer cells acquire the multidrug resistance (MDR) phenotype, and is associated with poor clinical outcome in patients. In an effort to develop MDR-reversal agents, we synthesized and evaluated a series of thiophenylbenzofuran derivatives (4-31) as P-gp inhibitors, among which compounds 4, 10, and 14 represented the optimal agent in reversing the MDR phenotype. These P-gp inhibitors were dramatically effective than verapamil in sensitizing the human ABCB1-overexpressing ABCB1/Flp-In™-293 cells and MDR KBvin cells to a series of chemotherapeutic agents, including vincristine and paclitaxel, as manifested by multi-fold decreases in the respective IC50 values to therapeutically attainable levels.

Targeting YAP Degradation by a Novel 1,2,4-Oxadiazole Derivative via Restoration of the Function of the Hippo Pathway.

Recent evidence has linked the dysregulation of the Hippo pathway to tumorigenesis and cancer progression due to its pivotal role in regulating the stability of the oncoprotein YAP. Based on an unexpected finding from the SAR study of a recently reported oxadiazole-based EGFR/c-Met dual inhibitor (compound 1), we identified a closely related derivative, compound 2, which exhibited cogent antitumor activities while devoid of compound 1's ability to promote EGFR/c-Met degradation. Compound 2 acted, in part, by facilitating YAP degradation through activation of its upstream kinase LATS1. However, it did not alter the phosphorylation status of MST1/2, a LATS1 kinase, suggesting an alternative mechanism for LATS1 activation. Orally administered compound 2 was effective in suppressing MDA-MB-231 xenograft tumor growth while exhibiting a satisfactory safety profile. From a therapeutic perspective, compound 2 might help foster new therapeutic strategies for cancer treatment by restoring the Hippo pathway regulatory function to facilitate YAP degradation.

A Novel pH-Tunable Secondary Conformation Containing Mixed Micellar System in Anticancer Treatment.

In this study, for the first time, we precisely assembled the poly-γ-benzyl-l-glutamate and an amphiphilic copolymer d-α-tocopherol polyethylene glycol succinate into a mixed micellar system for the embedment of the anticancer drug doxorubicin. Importantly, the intracellular drug-releasing behaviors could be controlled by changing the secondary structures of poly-γ-benzyl-l-glutamate via the precise regulation of the buffer's pH value. Under neutral conditions, the micellar architectures were stabilized by both α-helix secondary structures and the microcrystalline structures. Under acidic conditions (pH 4.0), the interior structures transformed into a coil state with a disordered alignment, inducing the release of the loaded drug. A remarkable cytotoxicity of the Dox-loaded mixed micelles was exhibited toward human lung cancer cells in vitro. The internalizing capability into the cancer cells, as well as the intracellular drug-releasing behaviors, were also identified and observed. The secondary structures containing Dox-loaded mixed micelles had an outstanding antitumor efficacy in human lung cancer A549 cells-bearing nude mice, while little toxicities occurred or interfered with the hepatic or renal functions after the treatments. Thus, these pH-tunable α-helix-containing mixed micelles are innovative and promising for controlled intracellular anticancer drug delivery.

Development of Novel Irreversible Pyruvate Kinase M2 Inhibitors.

As cancer cells undergo metabolic reprogramming in the course of tumorigenesis, targeting energy metabolism represents a promising strategy in cancer therapy. Among various metabolic enzymes examined, pyruvate kinase M2 type (PKM2) has received much attention in light of its multifaceted function in promoting tumor growth and progression. In this study, we reported the development of a novel irreversible inhibitor of PKM2, compound 1, that exhibits a differential tumor-suppressive effect among an array of cancer cell lines. We further used a clickable activity-based protein profiling (ABPP) probe and SILAC coupled with LC-MS/MS to identify the Cys-317 and Cys-326 residues of PKM2 as the covalent binding sites. Equally important, compound 1 at 10 mg/kg was effective in suppressing xenograft tumor growth in nude mice without causing acute toxicity by targeting both metabolic and oncogenic functions. Together, these data suggest its translational potential to foster new strategies for cancer therapy.

Alternative splicing in human cancer cells is modulated by the amiloride derivative 3,5-diamino-6-chloro-N-(N-(2,6-dichlorobenzoyl)carbamimidoyl)pyrazine-2-carboxide.

Alternative splicing (AS) is a process that enables the generation of multiple protein isoforms with different biological properties from a single mRNA. Cancer cells often use the maneuverability conferred by AS to produce proteins that contribute to growth and survival. In our previous studies, we identified that amiloride modulates AS in cancer cells. However, the effective concentration of amiloride required to modulate AS is too high for use in cancer treatment. In this study, we used computational algorithms to screen potential amiloride derivatives for their ability to regulate AS in cancer cells. We found that 3,5-diamino-6-chloro-N-(N-(2,6-dichlorobenzoyl)carbamimidoyl)pyrazine-2-carboxamide (BS008) can regulate AS of apoptotic gene transcripts, including HIPK3, SMAC, and BCL-X, at a lower concentration than amiloride. This splicing regulation involved various splicing factors, and it was accompanied by a change in the phosphorylation state of serine/arginine-rich proteins (SR proteins). RNA sequencing was performed to reveal that AS of many other apoptotic gene transcripts, such as AATF, ATM, AIFM1, NFKB1, and API5, was also modulated by BS008. In vivo experiments further indicated that treatment of tumor-bearing mice with BS008 resulted in a marked decrease in tumor size. BS008 also had inhibitory effects in vitro, either alone or in a synergistic combination with the cytotoxic chemotherapeutic agents sorafenib and nilotinib. BS008 enabled sorafenib dose reduction without compromising antitumor activity. These findings suggest that BS008 may possess therapeutic potential for cancer treatment.

Tanshinone IIA inhibits angiogenesis in human endothelial progenitor cells in vitro and in vivo.

Accumulating evidence reports that bone marrow-derived endothelial progenitor cells (EPCs) regulate angiogenesis, postnatal neovascularization and tumor metastasis. It has been suggested that understanding the molecular targets and pharmacological functions of natural products is important for novel drug discovery. Tanshinone IIA is a major diterpene quinone compound isolated from Danshen (Salvia miltiorrhiza) and is widely used in traditional Chinese medicine (TCM). Evidence indicates that tanshinone IIA modulates angiogenic functions in human umbilical vein endothelial cells. However, the anti-angiogenic activity of tanshinone IIA in human EPCs has not been addressed. Here, we report that tanshinone IIA dramatically suppresses vascular endothelial growth factor (VEGF)-promoted migration and tube formation of human EPCs, without cytotoxic effects. We also show that tanshinone IIA markedly inhibits VEGF-induced angiogenesis in the chick embryo chorioallantoic membrane (CAM) model. Importantly, tanshinone IIA significantly attenuated microvessel formation and the expression of EPC-specific markers in the in vivo Matrigel plug assay in mice. Further, we found that tanshinone IIA inhibits EPC angiogenesis through the PLC, Akt and JNK signaling pathways. Our report is the first to reveal that tanshinone IIA reduces EPC angiogenesis both in vitro and in vivo. Tanshinone IIA is a promising natural product worthy of further development for the treatment of cancer and other angiogenesis-related pathologies.

Structure-activity relationship study of novel 2-aminobenzofuran derivatives as P-glycoprotein inhibitors.

Treatment of cancer patients with chemotherapeutic drugs is often associated with the occurrence of tumors with a multidrug resistance (MDR). Furthermore, the relation between overexpression of P-glycoprotein (P-gp) and resistant cancers has been well established. In this study, novel 2-aminobenzofuran derivatives were synthesized and tested for their ability to modulate P-gp mediated multidrug resistance (MDR) in vitro. The most potent compound, 43, increased P-gp inhibitory activity at 5 µM by 11.12-fold and was 3.6-fold stronger than verapamil. Furthermore, 43 can sensitize Flp-In™-293/MDR cells toward vincristine, paclitaxel and doxorubicin by 17.95-fold, 13.68-fold and 26.43-fold at 2.5 µM, respectively. 43 also can sensitize the resistant cancer cell line KBvin toward vincristine, paclitaxel and doxorubicin by 246.43-fold, 38.72-fold and 5.16-fold at 2.5 µM, respectively. In conclusion, important aspects for developing potent P-gp inhibitors have been emphasized in this study, providing a starting point for the further structural optimization of P-gp inhibitors.

A novel benzofuran derivative, ACDB, induces apoptosis of human chondrosarcoma cells through mitochondrial dysfunction and endoplasmic reticulum stress.

Chondrosarcoma is one of the bone tumor with high mortality in respond to poor radiation and chemotherapy treatment. Here, we analyze the antitumor activity of a novel benzofuran derivative, 2-amino-3-(2-chlorophenyl)-6-(4-dimethylaminophenyl)benzofuran-4-yl acetate (ACDB), in human chondrosarcoma cells. ACDB increased the cell apoptosis of human chondrosarcomas without harm in chondrocytes. ACDB also enhanced endoplasmic reticulum (ER) stress, which was characterized by varieties in the cytosolic calcium levels and induced the expression of glucose-regulated protein (GRP) and calpain. Furthermore, the ACDB-induced chondrosarcoma apoptosis was associated with the upregulation of the B cell lymphoma-2 (Bcl-2) family members including pro- and anti-apoptotic proteins, downregulation of dysfunctional mitochondria that released cytochrome C, and subsequent activation of caspases-3. In addition, the ACDB-mediated cellular apoptosis was suppressed by transfecting cells with glucose-regulated protein (GRP) and calpain siRNA or treating cells with ER stress chelators and caspase inhibitors. Interestingly, animal experiments illustrated a reduction in the tumor volume following ACDB treatment. Together, these results suggest that ACDB may be a novel tumor suppressor of chondrosarcoma, and this study demonstrates that the novel antitumor agent, ACDB, induced apoptosis by mitochondrial dysfunction and ER stress in human chondrosarcoma cells in vitro and in vivo.

BL-038, a Benzofuran Derivative, Induces Cell Apoptosis in Human Chondrosarcoma Cells through Reactive Oxygen Species/Mitochondrial Dysfunction and the Caspases Dependent Pathway.

Chondrosarcoma is a highly malignant cartilage-forming bone tumor that has the capacity to invade locally and cause distant metastasis. Moreover, chondrosarcoma is intrinsically resistant to conventional chemotherapy or radiotherapy. The novel benzofuran derivative, BL-038 (2-amino-3-(2,6-dichlorophenyl)-6-(4-methoxyphenyl)benzofuran-4-yl acetate), has been evaluated for its anticancer effects in human chondrosarcoma cells. BL-038 caused cell apoptosis in two human chondrosarcoma cell lines, JJ012 and SW1353, but not in primary chondrocytes. Treatment of chondrosarcoma with BL-038 also induced reactive oxygen species (ROS) production. Furthermore, BL-038 decreased mitochondrial membrane potential (MMP) and changed mitochondrial-related apoptosis, by downregulating the anti-apoptotic activity members (Bcl-2, Bcl-xL) and upregulating pro-apoptotic members (Bax, Bak) of the B-cell lymphoma 2 (Bcl-2) family of proteins, key regulators of the apoptotic machinery in cells. These results demonstrate that in human chondrosarcoma cells, the apoptotic and cytotoxic effects of BL-038 are mediated by the intrinsic mitochondria-mediated apoptotic pathway, which in turn causes the release of cytochrome c, the activation of caspase-9 and caspase-3, and the cleavage of poly (ADP-ribose) polymerase (PARP), to elicit apoptosis response. Our results show that the benzofuran derivative BL-038 induces apoptosis in chondrosarcoma cells.

Synthesis and bioevaluation of novel benzodipyranone derivatives as P-glycoprotein inhibitors for multidrug resistance reversal agents.

Multidrug resistance (MDR) is a phenomenon in which cells become resistant to structurally and mechanistically unrelated drugs, and it is one of the emerging problems in cancer therapy today. The relation between overexpression of the ABC transporter subfamily B member 1 (ABCB1/P-glycoprotein) and resistant cancers has been well characterized. In the present study, we successfully synthesized 52 novel benzodipyranone analogs and evaluated for their P-gp inhibitory activity in a P-gp transfected cell line, ABCB1/Flp-In™-293. Among these derivatives, 5a bearing on the 3-methylphenyl substituent, displayed the most potent P-gp inhibitory activity, which can enable the increase of the intracellular accumulation of P-gp substrate Calcein-AM. 5a exhibited more potency on promoted anticancer drugs cytotoxicity by reversing P-gp-mediated drug resistance in both ABCB1/Flp-In™-293 and KBvin cell lines. In particular, the compound 5a sensitized ABCB1/Flp-In™-293 cells toward paclitaxel, vincristine, and doxorubicin by 16.1, 21.0, and 1.6-fold at 10 µM, respectively. Further, 5a dramatically sensitized the resistant cell line KBvin toward paclitaxel and vincristine by 23.1 and 29.7-fold at 10 µM, respectively. It's possible that its mechanism of MDR inhibition can restore the intracellular accumulation of drugs and eventually chemosensitize cancer cells to anticancer drugs and reduce ABCB1 mRNA expression level.

Tyrosol and its analogues inhibit alpha-melanocyte-stimulating hormone induced melanogenesis.

Melanin is responsible for skin color and plays a major role in defending against harmful external factors such as ultraviolet (UV) irradiation. Tyrosinase is responsible for the critical steps of melanogenesis, including the rate-limiting step of tyrosine hydroxylation. The mechanisms of action of skin hypopigmenting agents are thought to be based on the ability of a given agent to inhibit the activity of tyrosinase and, hence, down regulate melanin synthesis. Tyrosol and its glycoside, salidroside, are active components of Rhodiola rosea, and in our preliminary study we found that Rhodiola rosea extract inhibited melanogenesis. In this study, we examined the effects of tyrosol and its analogues on melanin synthesis. We found that treatment of B16F0 cells to tyrosol (1), 4-hydroxyphenylacetic acid (5), 3-hydroxyphenylacetic acid (6), 2-hydroxyphenylacetic acid (7), or salidroside (11) resulted in a reduction in melanin content and inhibition of tyrosinase activity as well as its expression. Tyrosol (1), 4-hydroxyphenylacetic acid (5) and 2-hydroxyphenylacetic acid (7) suppressed MC1R expression. Tyrosol (1), 4-hydroxyphenylacetic acid (5), 3-hydroxyphenylacetic acid (6), and 2-hydroxyphenylacetic acid (7) inhibited α-MSH induced TRP-1 expression, but salidroside (11) did not. All the compounds did not affect MITF and TRP-2 expression. Furthermore, we found that the cell viability of tyrosol (1), 4-hydroxyphenylacetic acid (5), 3-hydroxyphenylacetic acid (6), and 2-hydroxyphenylacetic acid (7) at concentrations below 4 mM and salidroside (11) at concentrations below 0.5 mM were higher than 90%. The compounds exhibited metal-coordinating interactions with copper ion in molecular docking with tyrosinase. Our results suggest that tyrosol, 4-hydroxyphenylacetic acid, 3-hydroxyphenylacetic acid, 2-hydroxyphenylacetic acid, and salidroside are potential hypopigmenting agents.