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 laboratoryadapted 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.As of February 2008, thirty-two anti-HIV drugs have been licensed by the US Food and Drug Administration (FDA) (http://www.fda.gov/oashi/aids/virals.html). These compounds include eleven HIV protease inhibitors, seventeen nucleoside and nonnucleoside reverse transcriptase (RT) inhibitors, one fusion inhibitor, one entry inhibitor (CCR5 co-receptor antagonist), one integrase inhibitor, and one multi-class combination product. Clinical combinations of these drugs, known as highly active antiretroviral therapy (HAART), have significantly reduced the morbidity and mortality of AIDS. However, increasing numbers of HIV/AIDS patients on HAART regimens fail to respond to current antiretroviral drugs due to the emergence of drugresistant HIV mutants. 1 Therefore, it is essential to develop additional potent anti-HIV drugs with novel mechanisms of action or resistance profiles different from those of current anti-HIV therapeutics.To whom correspondence should be addressed. Phone: 86-10-68181014. Fax: 86-10-6821-1656. E-mail: lanxieshi@yahoo.com; Phone: 919-962-0066. Fax: 919-966-3893. E-mail: khlee@unc.edu; Phone: 212-570-3058. Fax: 212-570-3099. E-mail: sjiang@nybloodcenter.org. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIn our prior studies, 3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (1, DCK, Figure 1) 2 and its analogs were identified as a novel class of anti-HIV agents with potent activity in H9 lymphocytes. Systematic modification of 1 provided more than 150 khellactone derivatives, including mono-, di-, and tri-substituted 1-analogs, and their SAR study results have been published. 3,4,5,6 Notably, mechanistic studies have demonstrated that 1 and its analogs do target HIV-1 RT; however, they do not interfere with its RNA-polymerase activity, but instead inhibit its DNA-dependent DNA polymerase activity. Thus, 1-analogs suppress the production of double-stranded viral DNA from a single-stranded DNA intermediate, 7 in stark contrast to current HIV-1 RT inhibitors that block the generation of single-stranded...
Twenty-six unsymmetrical biphenyls were synthesized and evaluated for cytotoxic activity against DU145, A547, KB and KB-Vin tumor cell lines. Three compounds 27, 35 and 40 showed very potent activity against the HTCL panel with an IC 50 value range of 0.04-3.23 µM. In addition, fourteen active compounds were all more potent against the drug-resistant KB-Vin cell line than the parental KB cell line. Preliminary SAR analysis indicated that two bulky substituents on the 2,2′-positions of unsymmetrical biphenyl skeleton are necessary and crucial for in vitro anticancer activity, thus providing a good starting point to develop unsymmetrical biphenyls as novel anticancer agents. KeywordsUnsymmetrical biphenyls; Suzuki coupling reaction; Anticancer agents Natural products continue to play a highly significant role today in the discovery and development of new drugs, new leads and new chemical entities. This fact is particularly evident in the areas of cancer and infectious diseases, where over 60% and 75% of drugs, respectively, are of natural origin. 1,2 Dibenzocyclooctandiene lignans have been identified as major bioactive constituents from the traditional Chinese medicinal plant Schizandra chinese and show a wide variety of interesting biological activities, 3, 4 including antiviral, 5 anticancer, 6, 7 hepatoprotective, 8 and anti-inflammatory. 9 Recently, it was also reported that several dibenzocyclooctadiene lignans, such as gomisin A, schisandrins A and B, and schisantherin A, have activity against cancer multidrug resistance mediated by P-glycoprotein (P-gp) and effectively restore the action of anticancer drugs, 10-12 such as vinblastine, daunorubicin, doxorubicin, and VP-16. *Corresponding author. Tel: 86-10-6931690, fax: 86 10 66931690, e-mail address: lanxieshi@yahoo.com. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Figure 1, and this feature is crucial for biological activity. Structural simplification of the symmetrical wuweizi C to simpler biphenyl analogs led to the anti-hepatotoxic (liver injury) drugs α-DDB (methyl 4,4′-dimethoxy-5,6,5′, 6′-dimethylenedioxy biphenyl-2,2-dicarboxylate) and bicyclol (Figure 1), which are widely used medicinally in China and Asia. In our current study, we decided to focus on unsymmetrical biphenyls, as such compounds have not been previously well explored for cytotoxic activity. NIH Public AccessOur goal was to identify novel biphenyl leads with potent anticancer effects, hopefully with activity against multidrug resistance.Herein, we report the synthesis of twenty-six unsymmetrical biphenyl compounds (18-43) and their...
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