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Twelve novel 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid(CDDO) derivatives were designed and synthesized(9a-91) by introducing different heterocyclic rings to 17-COOH of CDDO through various linkers.Their structures were determined by ESI-MS,IR and 1 H NMR.The antiproliferative activity of the synthetic derivatives against human cancer cells HCT-116,A549 and HepG2 was evaluated by MTT assay.Several compounds showed potent inhibitory activities against test cell lines.Among them,compound 9c showed more potent antiproliferative activity than the CDDO-imidazolide (CDDO-Im).Moreover,rat plasma stability assay showed that compound 9c was more stable than CDDO-Im.
ABSTRACT
@#In order to search for new anti-inflammatory agents with strong activity and less toxicity relative to CDDO-Me, the ester prodrugs 2-8 of CDDO-Me were synthesized by treatment of oleanolic acid(OA)with DMF/K2CO3 to generate 1, followed by esterification of 1 with various aliphatic and aromatic carboxylic acids, respectively. All the target compounds showed strong inhibitory effects on LPS-induced NO production in RAW 264. 7 cells. Among them, compounds 2 and 7 possessed the most potent inhibitory effects with IC50=(2. 34±0. 67)and(3. 83±0. 97)nmol/L, respectively. Moreover, MTT assay indicated that all the target compounds(2-8)displayed much weaker anti-proliferative activity against RAW 264. 7 cell lines than CDDO-Me, suggesting that they may be less toxic than CDDO-Me.
ABSTRACT
Objective To investigate the effects and mechanism of pre-treatment with an Nrf2 inducer dh404 on renal ischemia reperfusion injury in rats.Methods Thirty SD rats were divided into three groups using completely randomized digital table,dh404 was dissolved in sesame oil and was given orally 1.5 mg/kg the night before procedures and 5 hours before procedures.Rats in group Sham received no treatment of ischemic reperfusion.In group IR and group dh404,the renal ischemia reper-fusion (IR)model was established,24 hours after IR,the levels of serum creatininc (Cr)and urea ni-trogen (BUN),the activities of superoxide dismutase (SOD)and the content of malonaldehyde (MDA)in serum were measured,and hematoxylin eosin(HE)staining observe the changes in renal structure,the levels of γ-glutamate-cysteine ligase catalytic (GCLC)and modifier (GCLM)subunit, the expression of NF-κB,COX-2 and eNOS were measured.Results Compared with group Sham,the values of Cr,BUN in group IR and group dh404 were significantly higher (P <0.05).Compared to the group IR,the group dh404 Cr,BUN values significantly decreased after reperfusion for 24 h(P <0.05 ).Compared to group Sham,group IR SOD activity decreased,while the value of MDA increased(P <0.05 ).Compared to group IR,group dh404 had much higher SOD activity,while the value of MDA significantly decreased.Observed with optical microscopy,compared to group Sham, the renal tubular injury of group IR was obvious.Compared to group IR,group dh404 significantly reduced tubular injury.Compared to group IR,the levels of GCLC and modifier GCLM subunit were higher,while there were no significant differences of levels among NF-κB,COX-2 and eNOS. Conclusion Pre-treatment with an Nrf2 inducer dh404 can protect the kidney from IRI through possi-bly reducing IRI kidney oxidative stress.
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@#The novel oleanolic acid derivatives 2a-2e were synthesized by introducing an α, β-unsaturated ketone moiety to C-ring of oleanolic acid(OA)via a nine-step reaction sequence, yielding an active CDDO-Me analogue(1), followed by coupling of C3-OH of 1 with various aliphatic and aromatic carboxylic acids, respectively. Derivatives 3a-3e were synthesized by substituting C-1 of compounds 2a-2e with bromine. The target compounds were characterized by IR, MS and 1H NMR spectra. All the target compounds showed strong inhibitory effects against two tumor cell lines(HepG2 and A549)to a varying extent. The anti-proliferative activities of active compounds 3b and 3c(IC50=6. 13±1. 16 μmol/L and IC50=5. 49±1. 03 μmol/L, respectively)against HepG2 and A549 were more potent than compound 1 and comparable to the positive control CDDO-Me. In addition, all the target compounds displayed much weaker anti-proliferative activity against the two tumor cell lines than that against normal BEAS-2B cells. Compound 3c showed ten-fold selective inhibition against HepG2 relative to BEAS-2B cells, and is thus worthy of further study.
ABSTRACT
OBJECTIVE: To systematically summarize studies on the synthesis of 2-cyano-3, 12-dioxoolean-l, 9-dien-28-oic acid (CDDO), structural modification and structure-activity relationship(SAR) of CDDO and its derivatives in the positions of A, C rings, C-2, C-17 and others. METHODS: Based on the newest research reports at home and abroad, the SARs of CDDO and its derivatives were analyzed and summarized. RESULTS AND CONCLUSION: SAR studies of CDDO and its derivatives can help us use them as references for the development of drugs with better actitivity and selectivity.