Haiyan Lin

Synthesis and biological evaluation of JL-A7 derivatives as potent ABCB1 inhibitors

Cancer chemotherapy failure is often due to the overexpression of ATP-binding cassette (ABC) transporters (particularly ABCB1), resulting in a variety of structurally and pharmacologically unrelated drugs efflux. The multidrug resistance (MDR) phenomenon could be reversed by ABCB1 inhibitors. Now, JL-A7 as the lead compound based on a triazol-N-ethyl-tetrahydroisoquinoline scaffold, 18 compounds were designed and synthesized. Substitution in para positions yielded high activities toward ABCB1. Moreover, compound 5 could effectively block the drug efflux function of ABCB1 and increase the accumulation of anti-cancer drugs to achieve effective treatment concentration in MDR cells.

Synthesis and Preliminary Biological Evaluation of Capsaicin Derivatives as Potential Analgesic Drugs

A series of capsaicin derivatives were designed and synthesized, including 10 compounds which are the combination of capsaicin and dihydro capsaicin with ibuprofen through bridge chain. Preliminary biological tests suggested that some compounds had both anti-inflammatory activity and analgesic activity. And their pungency was lower. Based on these results, some of these molecules can be considered as lead candidates for the further development of analgesic drugs.

Evaluation of Anti‐inflammatory and Analgesic Effects of Synthesized Derivatives of Ibuprofen

Inflammatory and pain are major areas for drug discovery. Current analgesic drugs often cause a number of side‐effects. In the present study, we modified carboxylic acid group of ibuprofen, one of non‐steroidal anti‐inflammatory drugs, based on the common structure of transient receptor potential vanilloid type 1 antagonists which are considered as new candidates for analgesic drugs, and synthesized several derivatives of ibuprofen. Comprehensive evaluations of the pharmacological properties of these compounds were investigated. Compound 17 showed weak cyclooxygenase inhibition and exhibited strong transient receptor potential vanilloid type 1 antagonistic activity. It was found to be capable of blocking noxious thermal nociception and capsaicin‐induced nociception in mice. Besides, 17 showed less ulcerogenic action than ibuprofen did and had no hyperthermia side‐effect compared with common transient receptor potential vanilloid type 1 antagonists. Therefore, it suggested that 17 could be used as a safe alternative analgesic candidate for pain treatment.

A novel mitochondria-targeting fluorescent probe for hydrogen sulfide in living cells

A novel mitochondria‐targeting fluorescent probe compound S‐N3 for hydrogen sulfide (H2S) in living cells has been designed and synthesized in this study. This article contained the chemosynthesis and some studies on bioactivity of the target compound in living cells. Compound S‐N3 is easy to synthesize and can remain stable under the effect of pH, system and photostability. In addition, it shows low cytotoxicity in cell imaging. And it can react with H2S highly selective in PBS or FBS solution, which would cause the obvious increase in fluorescence intensity. Therefore, the low‐cost detection method for H2S is allowed for monitoring the quantity of H2S existed in the mitochondria.

Synthesis and biological evaluation of novel aliphatic acid-conjugated antimicrobial peptides as potential agents with anti-tumor, multidrug resistance-reversing activity and enhanced stability

Compared with traditional anti-tumor drugs, antimicrobial peptides as novel anti-tumor agents have prominent advantages of higher specificity and circumvention of multi-drug resistance. BP100 is a multifunctional membrane-active peptide with high antimicrobial activity. Taking BP100 as a lead peptide, we designed and synthesized a series of aliphatic chain-conjugated peptides through solid-phase synthesis. Biological evaluation revealed that these peptides exhibited better anti-cancer activity than BP100. Further investigations revealed that these peptides could disrupt the cell membrane and trigger the cytochrome C release into cytoplasm, which ultimately resulted in apoptosis. Meanwhile, these peptides also exhibited effective anti-tumor activity against multidrug resistant cells and had multidrug resistance-reversing effect. Additionally, conjugation of aliphatic acid to those peptides could enhance their stability in plasma. In conclusion, aliphatic acid-modified peptides might be promising anti-tumor agents for cancer therapy.

Synthesis of Carbamide Derivatives Bearing Tetrahydroisoquinoline Moieties and Biological Evaluation as Analgesia Drugs in Mice

Transient receptor potential vanilloid 1 (TRPV1) is a ligand‐gated non‐selective cation channel that is considered to be an important pain integrator. Tetrahydroisoquinoline, the prototypical antagonist of TRPV1, has a clear therapeutic potential. Here, a series of carbamide derivatives of tetrahydroisoquinoline were designed and synthesized. Preliminary biological tests suggested that the compounds I 1, I 2, and I 9 had favorable TRPV1 antagonism activity. In further studies, I 1 exhibited better antinociceptive activity than the positive control BCTC in diverse pain models. All of these results suggested that I 1 can be considered as the lead candidate for the further development of antinociceptive drugs.

Pro-apoptotic cationic host defense peptides rich in lysine or arginine to reverse drug resistance by disrupting tumor cell membrane

Host defense peptides have been demonstrated to exhibit prominent advantages in cancer therapy with selective binding ability toward tumor cells via electrostatic attractions, which can overcome the limitations of traditional chemotherapy drugs, such as toxicity on non-malignant cells and the emergence of drug resistance. In this work, we redesigned and constructed a series of cationic peptides by inserting hydrophobic residues into hydrophilic surface or replacing lysine (K) with arginine (R), based on the experience from the preliminary work of host defense peptide B1. In-depth studies demonstrated that the engineered peptides exhibited more potent anti-cancer activity against various cancer cell lines and much lower toxicity to normal cells compared with B1. Further investigation revealed that compounds I-3 and I-7 could act on cancer cell membranes and subsequently alter the permeability, which facilitated obvious pro-apoptotic activity in paclitaxel-resistant cell line (MCF-7/Taxol). The result of mitochondrial membrane potential assay (ΔΨm) demonstrated that the peptides induced ΔΨm dissipation and mitochondrial depolarization. The caspase-3 cellular activity assay showed that the anti-cancer activity of peptides functioned via caspase-3-dependent apoptosis. The study yielded compound I-7 with superior properties for antineoplastic activity in comparison to B1, which makes it a promising potential candidate for cancer therapy.