Discovery of novel ocotillol derivatives modulating glucocorticoid receptor/NF-κB signaling for the treatment of sepsis.

Glucocorticoids (GCs) have been used in the treatment of sepsis because of their potent anti-inflammatory effects. However, their clinical efficacy against sepsis remains controversial because of glucocorticoid receptor (GR) downregulation and side effects. Herein, we designed and synthesized 30 ocotillol derivatives and evaluated their anti-inflammatory activities. Ocotillol 24(R/S) differential isomers were stereoselective in their pharmacological action. Specifically, 24(S) derivatives had better anti-inflammatory activity than their corresponding 24(R) derivatives. Compound 20 most effectively inhibited NO release (85.97% reduction), and it exerted dose-dependent inhibitory effects on interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels. Mechanistic studies revealed that compound 20 reduces the degradation of GR mRNA and GR protein. Meanwhile, compound 20 inhibited the activation of nuclear factor-κB (NF-κB) signaling, thereby inhibiting the nuclear translocation of p65 and attenuating the inflammatory response. In vivo studies revealed that compound 20 attenuated hepatic, pulmonary, and renal pathology damage in mice with sepsis and suppressed the production of inflammatory mediators. These results indicated that compound 20 is a promising lead compound for designing and developing anti-sepsis drugs.

Design, synthesis, and biological evaluation of ocotillol derivatives fused with 2-aminothiazole via A-ring as modulators of P-glycoprotein-mediated multidrug resistance.

Overexpression of P-glycoprotein (P-gp) plays a key role in the development of multidrug resistance (MDR), the major reason for the failure of chemotherapy in clinics. Ocotillol and its derivatives had been reported with good P-gp-mediated tumor MDR reversal activity in vitro. Herein, a series of ocotillol derivatives fused with 2-aminothiazole (2-AT) via A-ring were designed and synthesized to further improve the tumor MDR reversal potency. These compounds were evaluated for their MDR reversal activity against the KBV cells by MTT assay. Among them, the most promising derivative against P-gp-mediated MDR was compound 12 with 2-AT and glycine in the A-ring. Rhodamine123 (Rh123) accumulation assay, Western blot assay, and P-gp-Glo™ assay showed that compound 12 efficiently inhibited the efflux function of P-gp by stimulating P-gp ATPase rather than downregulating its expression. Moreover, compound 12 sensitized KBV cells to paclitaxel arrested cells in the G2/M phase and induced cell apoptosis. Importantly, compound 12 significantly inhibited the growth of KBV cell-derived xenograft tumors in nude mice by increasing the sensitivity of paclitaxel in vivo. Finally, the structure-activity relationships (SARs) of ocotillol derivatives were further investigated. In summary, compound 12 has the potential to overcome MDR in cancer caused by P-gp.