Anti-Human Immunodeficiency Virus Activity, Cross-Resistance, Cytotoxicity, and Intracellular Pharmacology of the 3′-Azido-2′,3′-Dideoxypurine Nucleosides

Sluis‐Cremer, Nicolas; Koontz, Dianna; Bassit, Leda; Hernandez-Santiago, Brenda I.; Detorio, Mervi; Rapp, Kimberly L.; Amblard, Franck; Bondada, Lavanya; Grier, Jason; Coats, Steven J.; Schinazi, Raymond F.; Mellors, John W.

doi:10.1128/aac.00392-09

Cited by 17 publications

(21 citation statements)

References 24 publications

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“…The mixture was stirred under H 2 for 12 h. After filtering the filtrate was evaporated and isolated by silica gel decompression column with CH 2 …”

Section: Synthesis Of 2-amino-6-(1-piperidinyl)-9-(2'3'-dideoxy-β-d-mentioning

confidence: 99%

“…NRTIs are metabolically converted by host cell kinases to corresponding triphosphate forms and inhibit virus replication by acting as chain terminators of RT-mediated DNA synthesis. [1,2] In the effort to search novel NRTIs with low toxicity and favorable resistance profiles, 2',3'-dideoxynucleoside (ddN) and 2',3'-didehydro-2',3'-dideoxynucleoside (D4N) have been attracting wide attention since ddN was found behaving anti-human III T-lymphocyte virus activity in 1986. [3] Previous research had demonstrated that many of the ddN and D4N exhibited good activities against HBV and HIV.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Anti‐HIV Activity of a Series of 6‐Modified 2′,3′‐Dideoxyguanosine and 2′,3′‐Didehydro‐2′,3′‐dideoxyguanosine Analogs

et al. 2013

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In search of potential 2',3'-dideoxyguanosine (ddG) and 2',3'-didehydro-2',3'-dideoxyguanosine (D4G) prodrugs, a series of 6-modified ddG, D4G analogs were synthesized and evaluated for their anti-HIV activities and cytotoxities in cell-based assays. All analogs showed low cytotoxicities and some of them displayed benign anti-HIV activities. The active triphosphate forms in vivo, ddGTP and D4TTP, were also synthesized by a novel and facile "one-pot" method. The recognition of ddGTP and D4TTP by Taq, Therminater DNA polymerase and HIV reverse transcriptase (RT) incorporated in DNA/RNA strands were investigated by a non-radioactivity method and K m were determined.

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“…The mixture was stirred under H 2 for 12 h. After filtering the filtrate was evaporated and isolated by silica gel decompression column with CH 2 …”

Section: Synthesis Of 2-amino-6-(1-piperidinyl)-9-(2'3'-dideoxy-β-d-mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and Anti‐HIV Activity of a Series of 6‐Modified 2′,3′‐Dideoxyguanosine and 2′,3′‐Didehydro‐2′,3′‐dideoxyguanosine Analogs

et al. 2013

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“…To confirm the genotypes of virus populations, viral RNA was extracted from culture supernatants by using oligo(dT) 25 Dynabeads (Invitrogen, Carlsbad, CA) according to the manufacturer's instructions and treated with 1 IU/l of DNase I for 2 h. The RNA was converted into cDNA and amplified using the SuperScript III one-step RT-PCR system with Platinum Taq DNA polymerase (Invitrogen). The entire coding region of RT was amplified using the forward primer 5Ј-GCTCTATTAGATACAGGAGCAGATGA T-3Ј and the reverse primer 5Ј-CCTTCTAAATGTGTACAATCTAGTTGCCA T-3Ј.…”

Section: Methodsmentioning

confidence: 99%

“…Previously, our group reported that the nucleoside base was a major determinant for HIV-1 resistance mechanisms (17,23,25). Specifically, we demonstrated that AZT-resistant HIV-1 did not exhibit cross-resistance to the 3Ј-azido-2Ј,3Ј-dideoxypurines: 3Ј-azido-2Ј,3Ј-dideoxyguanosine (3Ј-azido-ddG) and 3Ј-azido-2Ј,3Ј-dideoxyadenosine (3Ј-azido-ddA) (17,23).…”

mentioning

confidence: 99%

The Base Component of 3′-Azido-2′,3′-Dideoxynucleosides Influences Resistance Mutations Selected in HIV-1 Reverse Transcriptase

Meteer¹,

Koontz²,

Asif³

et al. 2011

Antimicrob Agents Chemother

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We recently reported that HIV-1 resistant to 3-azido-3-deoxythymidine (AZT) is not cross-resistant to 3-azido-2,3-dideoxypurines. This finding suggested that the nucleoside base is a major determinant of HIV-1 resistance to nucleoside analogs. To further explore this hypothesis, we conducted in vitro selection experiments by serial passage of HIV-1 LAI in MT-2 cells in increasing concentrations of 3-azido-2,3-dideoxyguanosine (3-azido-ddG), 3-azido-2,3-dideoxycytidine (3-azido-ddC), or 3-azido-2,3-dideoxyadenosine (3-azidoddA). 3-Azido-ddG selected for virus that was 5.3-fold resistant to 3-azido-ddG compared to wild-type HIV-1 LAI passaged in the absence of drug. Population sequencing of the entire reverse transcriptase (RT) gene identified L74V, F77L, and L214F mutations in the polymerase domain and K476N and V518I mutations in the RNase H domain. However, when introduced into HIV-1 by site-directed mutagenesis, these 5 mutations only conferred ϳ2.0-fold resistance. Single-genome sequencing analyses of the selected virus revealed a complex population of mutants that all contained L74V and L214F linked to other mutations, including ones not identified during population sequencing. Recombinant HIV-1 clones containing RT derived from single sequences exhibited 3.2-to 4.0-fold 3-azido-ddG resistance. In contrast to 3-azido-ddG, 3-azido-ddC selected for the V75I mutation in HIV-1 RT that conferred 5.9-fold resistance, compared to the wild-type virus. Interestingly, we were unable to select HIV-1 that was resistant to 3-azido-ddA, even at concentrations of 3-azido-ddA that yielded high intracellular levels of 3-azido-ddA-5-triphosphate. Taken together, these findings show that the nucleoside base is a major determinant of HIV-1 resistance mechanisms that can be exploited in the design of novel nucleoside RT inhibitors.

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“…Richard W. Spjut opines that while cytotoxicity to tumor cell lines and antitumor activity for a plant taxon cannot be known a priori based on one reported ethnomedical application versus another, comparing literature review and ethnopharmacological field work in tandem with biological screening suggests in general that: (a) greater toxicity categories exhibit higher hit rates than all medicinal plants taken as one category and (b) certain categories had three (anthelminthics) to four (arrow poisons and homicidal agents) times the hit rates of plants screened from "random" collections (Spjut, 2005). Still it is not necessarily straightforward that maximizing cytotoxicity in prioritizing bioactive leads always catalyzes advancement in the US pharmaceutical pipeline, as evidenced by the development of antihepatitis C nucleoside analogues for instance, which was among the first preclinical pharmacological research to suggest that it may behoove scientists to emphasize leads that retain moderate activity while minimizing toxicity (Sluis-Cremer et al, 2009;Coats et al, 2014). Plants and other sources of bioactive metabolites may be ideally positioned to take advantage of the uncertain interplay between bioactivity and toxicity in the transition from preclinical to clinical evaluation of leads, given that they often produce a suite of closely related analogues.…”

Section: Anticancer Bioprospecting From Plants: Medical Ethnobotany Cmentioning

confidence: 99%

Revisiting the linkage between ethnomedical use and development of new medicines: A novel plant collection strategy towards the discovery of anticancer agents

Henkin¹,

Kongmany²,

Xayvue³

et al. 2017

J. Med. Plants Res.

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The Vietnam-Laos International Cooperative Biodiversity Group (ICBG) based at the University of Illinois at Chicago (UIC) catalyzed a country-wide network of medicinal plant preserves (MPP) and medicinal biodiversity preserves (MBP) now established in ten provinces of the Lao People's Democratic Republic (Lao PDR), which are relied upon as protected sources of ethnomedicines for local villagers and traditional healers. In collaboration with the Lao PDR's Institute of Traditional Medicine (ITM), our ongoing P01 Program Project (Ohio State University) examined the anticancer bioprospecting potential for two of the most exhaustively inventoried of these sites: the Bolikhamxay MPP and the Xiengkhouang MBP. Guided by prior voucher specimens sourced from these reserves, with an overwhelming emphasis on plants employed in traditional medicine, 201 distinct samples from 96 species were collected along with proper herbarium documentation. Aliquots of these plant samples were extracted in azeotropic ethanol and evaporated to dryness for initial biological evaluation. In six samples from six different species (2.99% of the collected samples and 6.25% of taxa), it was observed that extracts exhibited notable cytotoxicity against HT-29 colon adenocarcinoma cells. The wisdom behind the utilization of HT-29 cells in this preliminary biological screen is discussed. Furthermore, comparison of screening results based on longstanding considerations and ideological underpinnings of ethnobotanical vs. "random" biodiversity-based collection approaches is detailed herein. The results of this interdisciplinary study support the hypothesis that, by privileging the initial sample set in terms of human safety and pharmacological activity, ethnobotanically driven collection for biological screening efforts can produce leads unprecedented by the strict traditional usages of plants.

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Anti-Human Immunodeficiency Virus Activity, Cross-Resistance, Cytotoxicity, and Intracellular Pharmacology of the 3′-Azido-2′,3′-Dideoxypurine Nucleosides

Cited by 17 publications

References 24 publications

Synthesis and Anti‐HIV Activity of a Series of 6‐Modified 2′,3′‐Dideoxyguanosine and 2′,3′‐Didehydro‐2′,3′‐dideoxyguanosine Analogs

Synthesis and Anti‐HIV Activity of a Series of 6‐Modified 2′,3′‐Dideoxyguanosine and 2′,3′‐Didehydro‐2′,3′‐dideoxyguanosine Analogs

The Base Component of 3′-Azido-2′,3′-Dideoxynucleosides Influences Resistance Mutations Selected in HIV-1 Reverse Transcriptase

Revisiting the linkage between ethnomedical use and development of new medicines: A novel plant collection strategy towards the discovery of anticancer agents

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