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author:("Yu, dongle")
1.  Anti-AIDS agents 86. Synthesis and anti-HIV evaluation of 2′,3′-seco-3′-nor DCP and DCK analogues 
In a continuing study of novel anti-HIV agents with drug-like structures and properties, 30 1′-O-, 1′-S-, 4′-O- and 4′-substituted-2′,3′-seco-3′-nor DCP and DCK analogues (8–37) were designed and synthesized. All newly synthesized seco-compounds were screened against HIV-1NL4-3 and a multiple reverse transcriptase (RT) inhibitor-resistant (RTMDR) strain in the TZM-bl cell line, using seco-DCK (7) and 2-ethyl-DCP (4) as controls. Several compounds (14, 18, 19, 22–24, and 32) exhibited potent anti-HIV activity with EC50 values ranging from 0.93 to 1.93 μM and therapeutic index (TI) values ranging from 20 to 39. 1′-O-Isopropoxy-2′,3′-seco-3′-nor-DCP (12) showed the greatest potency among the newly synthesized compounds with EC50 values of 0.47 and 0.88 μM, and TI of 96 and 51, respectively, against HIV-1NL4-3 and RTMDR strains. The seco-compounds exhibited better chemical stability in acidic conditions compared with DCP and DCK compounds. Overall, the results suggested that seco-DCP analogues with simplified structures may be more favorable for development as novel anti-HIV candidates.
PMCID: PMC3183312  PMID: 21864952
2′, 3′-Seco-3′-nor-DCPs; Anti-HIV activity; Structure–activity relationship (SAR)
2.  Anti-AIDS agents 84†. Synthesis and anti-human immunodeficiency virus (HIV) activity of 2′-monomethyl-4-methyl- and 1′-thia-4-methyl-(3′R,4′R)-3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogs 
Bioorganic & medicinal chemistry  2010;18(20):7203-7211.
In a continuing investigation into the pharmacophores and structure-activity relationship (SAR) of (3′R,4′R)-3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) as a potent anti-HIV agent, 2′-monomethyl substituted 1′-oxa, 1′-thia, 1′-sulfoxide and 1′-sulfone analogs were synthesized and evaluated for inhibition of HIV-1 replication in H9 lymphocytes. Among them, 2′S-monomethyl-4-methyl DCK (5a) and 2′S-monomethyl-1′-thia-4-methyl DCK (7a) exhibited potent anti-HIV activity with EC50 values of 40.2 and 39.1 nM and remarkable therapeutic indexes of 705 and 1000, respectively, which were better than those of the lead compound DCK in the same assay. In contrast, the corresponding isomeric 2′R-monomethyl-4-methyl DCK (6) and 2′R-monomethyl-1′-thia-4-methyl DCK (8) showed much weaker inhibitory activity against HIV-1 replication. Therefore, the bioassay results suggest that the spatial orientation of the 2′-methyl group in DCK analogs can have important effects on anti-HIV activity of this compound class.
PMCID: PMC2949462  PMID: 20846868
2′-Monomethyl-4-methyl-(3′R, 4′R)-3′; 4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogs; 1′-Thia-4-methyl-(3′R,4′R)-3′; 4′-Di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogs; Anti-HIV activity; Structure-activity relationship (SAR)
3.  Anti-AIDS Agents 82: Synthesis of Seco-(3′R,4′R)-3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) Derivatives as Novel Anti-HIV Agents 
Bioorganic & medicinal chemistry  2010;18(12):4363-4373.
Thirteen novel seco-DCK analogs (4–16) with several new skeletons were designed, synthesized and screened for in vitro anti-HIV-1 activity. Among them, three compounds (5, 13, and 16) showed moderate activity, and compound 9 exhibited the best activity with an EC50 value of 0.058 μM and a therapeutic index (TI) of 1000. The activity of 9 was better than that of 4-methyl DCK (2, EC50: 0.126 μM, TI: 301.2) in the same assay. Additionally, 9 also showed antiviral activity against a multi-RT inhibitor-resistant strain (RTMDR), which is insensitive to most DCK analogs. Compared with 2, compound 9 has a less complex structure, fewer hydrogen-bond acceptors, and a reduced log P value. Therefore, it is likely to exhibit better ADME, and appears to be a promising new lead for further development as an anti-HIV candidate.
PMCID: PMC2905049  PMID: 20537902
Seco-DCK analogs; Anti-HIV agents
4.  Antitumor Agents. 272. Structure–Activity Relationships and In Vivo Selective Anti-Breast Cancer Activity of Novel Neo-tanshinlactone Analogs 
Journal of medicinal chemistry  2010;53(5):2299-2308.
Neo-tanshinlactone (1) and its previously reported analogs, such as 2, are potent and selective in vitro anti-breast cancer agents. The synthetic pathway to 2 was optimized from seven to five steps, with a better overall yield. Structure–activity relationships studies on these compounds revealed some key molecular determinants for this family of anti-breast agents. Several derivatives (19-21 and 24) exerted potent and selective anti-breast cancer activity with IC50 values of 0.3, 0.2, 0.1 and 0.1 μg/mL, respectively, against the ZR-75-1 cell lines. Compound 24 was two- to three-fold more potent than 1 against SK-BR-3 and ZR-75-1. Importantly, 21 exhibited high selectivity; it was 23 times more active against ZR-75-1 than MCF-7. Compound 20 had an approximately 12-fold ratio of SK-BR-3/MCF-7 selectivity. In addition, analog 2 showed potent activity against a ZR-75-1 xenograft model, but not PC-3 and MDA-MB-231 xenografts, as well as high selectivity against breast cancer cell line compared with normal breast tissue-derived cell lines. Further development of lead compounds 19-21 and 24 as clinical trial candidates is warranted.
PMCID: PMC2849726  PMID: 20148565
5.  Cytotoxic Phenanthrenequinones and 9,10-Dihydrophenanthrenes from Calanthe arisanensis 
Journal of natural products  2009;72(2):210-213.
Two new phenanthrenequinones, calanquinones B–C (2–3), four new 9,10-dihydrophenanthrenes, calanhydroquinones A–C (4–6), and calanphenanthrene A (7), along with five known compounds (1 and 8–11) were isolated from an EtOAc-soluble extract of Calanthe arisanensis through bioassay-guided fractionation. Their structures were identified from spectroscopic data, and the compounds were tested for in vitro cytotoxic activity against human lung (A549), prostate (PC-3 and DU145), colon (HCT-8), breast (MCF-7), nasopharyngeal (KB), and vincristine-resistant nasopharyngeal (KBVIN) cancer cell lines. Compound 1 showed the highest potency (EC50 < 0.5 μg/mL) against all seven cancer cell lines, with the greatest activity against breast cancer MCF-7 cells (EC50 < 0.02 μg/mL). Generally, except for 7, compounds 2–11 also showed significant cytotoxic activity (EC50 < 4μg/mL) against some cell lines (especially PC-3 and MCF-7) in the panel.
PMCID: PMC2880632  PMID: 19193043
6.  Anti-AIDS Agents 78 †. Design, Synthesis, Metabolic Stability Assessment, and Antiviral Evaluation of Novel Betulinic Acid Derivatives as Potent Anti-Human Immunodeficiency Virus (HIV) Agents 
Journal of medicinal chemistry  2009;52(10):3248-3258.
In a continuing study of potent anti-HIV agents, seventeen 28,30-disubstituted betulinic acid (BA, 1) derivatives, as well as seven novel 3,28-disubstituted BA analogs were designed, synthesized, and evaluated for in vitro antiviral activity. Among them, compound 21 showed an improved solubility and equal anti-HIV potency (EC50: 0.09 μM), when compared to HIV entry inhibitors 3b (IC9564) and 4 (A43-D). Using a cyclic secondary amine to form the C-28 amide bond increased the metabolic stability of the derivatives significantly in pooled human liver microsomes. The most potent compounds 47 and 48 displayed potent anti-HIV activity with EC50 values of 0.007 μM and 0.006 μM, respectively. These results are slightly better than that of bevirimat (2), which is currently in Phase IIb clinical trials. Compounds 47 and 48 should serve as attractive promising leads to develop next generation, metabolically stable, 3,28-disubstituted bifunctional HIV-1 inhibitors as clinical trials candidates.
PMCID: PMC2736638  PMID: 19388685
7.  Development and Preclinical Studies of Broad-spectrum Anti-HIV Agent (3′R,4′R)-3-Cyanomethyl-4-methyl-3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (3-Cyanomethyl-4-methyl-DCK) 
Journal of medicinal chemistry  2008;51(24):7689-7696.
In prior investigation, we discovered that (3'R,4'R)-3-cyanomethyl-4-methyl-3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (4, 3-cyanomethyl-4-methyl-DCK) showed promising anti-HIV activity. In these current studies, we developed and optimized successfully a practical ten-step synthesis for scale-up preparation to increase the overall yield of 4 from 7.8% to 32%. Furthermore, compound 4 exhibited broad-spectrum anti-HIV activity against wild-type and drug-resistant viral infection of CD4+ T cell lines as well as peripheral blood mononuclear cells by both laboratory-adapted and primary HIV-1 isolates with distinct subtypes and tropisms. Compound 4 was further subjected to in vitro and in vivo pharmacokinetic studies. These studies indicated that 4 has moderate cell permeability, moderate oral bioavailability and low systemic clearance. These results suggest that 4 should be developed as a promising anti-HIV agent for development as a clinical trial candidate.
PMCID: PMC2662438  PMID: 19053755
8.  Cytotoxic Calanquinone A from Calanthe arisanensis and Its First Total Synthesis 
Calanquinone A (1) was isolated from an EtOAc-soluble extract of Calanthe arisanensis through bioassay-guided fractionation. Its structure was identified by spectroscopic methods. Compound 1 showed potent cytotoxicity (EC50 < 0.5 µg/mL) against lung (A549), prostate (PC-3 and DU145), colon (HCT-8), breast (MCF7), nasopharyngeal (KB), and vincristine-resistant nasopharyngeal (KB-VIN) cancer cell lines, and interestingly, showed an improved drug resistance profile compared to paclitaxel. The total synthesis of 1 was also achieved and reported herein.
PMCID: PMC2551759  PMID: 18640035
9.  Synthesis and Proteasome Inhibition of Glycyrrhetinic Acid Derivatives 
Bioorganic & medicinal chemistry  2008;16(14):6696-6701.
This study discovered that glycyrrhetinic acid inhibited the human 20S proteasome at 22.3 µM. Esterification of the C-3 hydroxyl group on glycyrrhetinic acid with various carboxylic acid reagents yielded a series of analogs with marked improved potency. Among the derivatives, glycyrrhetinic acid 3-O-isophthalate (17) was the most potent compound with IC50 of 0.22 µM, which was approximately 100-fold more potent than glycyrrhetinic acid.
PMCID: PMC2579312  PMID: 18562200
Glycyrrhetinic acid; proteasome inhibitor; triterpene
10.  Anti-AIDS Agents 73: Structure-Activity Relationship Study and Asymmetric Synthesis of 3-O-Monomethylsuccinyl Betulinic Acid Derivatives 
3-O-3′(or 2′)-methylsuccinyl-betulinic acid (MSB) derivatives were separated by using recycle HPLC. The structures of four isomers were assigned by NMR and asymmetric synthesis. 3-O-3′S-Methylsuccinyl-betulinic acid (3′S-MSB, 4) exhibited potent anti-HIV activity with an EC50 value of 0.0087 μM and a TI value of 6.3×103, which is comparable to the data for bevirimat (DSB, PA-457), a current clinical trials drug that was also derived from betulinic acid. The anti-HIV potency of 4 was slightly better than that of AZT.
PMCID: PMC2140232  PMID: 17935987
11.  First Total Synthesis of Protoapigenone and its Analogs as Potent Cytotoxic Agents 
Journal of medicinal chemistry  2007;50(16):3921-3927.
Protoapigenone (1), isolated from Thelypteris torresiana, previously showed significant cytotoxic activity against five human cancer cell lines. In a continued structure-activity relationship study, the first total synthesis and modification of 1 were achieved. All synthesized compounds and related intermediates were evaluated for cytotoxic activity against five human cancer cell lines, HepG2, Hep3B, MDA-MB-231, MCF-7 and A549. Among them, 24 showed 2.2-14.2 fold greater cytotoxicity than 1 and naphthyl A-ring analogs remarkably enhanced the activity.
PMCID: PMC2587018  PMID: 17622129
12.  Anti-AIDS Agents 69.1 Moronic Acid and Other Triterpene Derivatives as Novel Potent Anti-HIV Agents 
Journal of medicinal chemistry  2006;49(18):5462-5469.
In a continuing structure-activity relationship study of potent anti-HIV agents, seven new triterpene derivatives were designed, synthesized, and evaluated for in vitro antiviral activity. Among them, moronic acid derivatives 19, 20 and 21 showed significant activity in HIV-1 infected H9 lymphocytes. Compounds 19 and 20 were also evaluated against HIV-1 NL4−3 and drug resistant strains in the MT-4 cell line. Compounds 19 and 20 showed better antiviral profiles than the betulinic acid analog 8 (PA-457), which has successfully completed a Phase IIa clinical trial. Compound 20 showed potent anti-HIV activity with EC50 values of 0.0085 μM against NL4−3, 0.021 μM against PI-R (a multiple protease inhibitor resistant strain), and 0.13 μM against FHR-2 (an HIV strain resistant to 8), respectively. The promising compound 20 has become a new lead for modification, and further development of 20-related compounds as clinical trial candidates is warranted.
PMCID: PMC2512972  PMID: 16942019

Results 1-12 (12)