Design, Synthesis and Anti Colon Cancer Activity Evaluation of Phosphorylated Derivatives of Lamivudine (3TC)
TL;DR: The novel phosphorylated derivatives of Lamivudine (5a-5l) as potential anti colon cancer agents are synthe- sized and among them 5a and 5b emerged as lead compounds with 0.003 μM and 0.0001 μM values.
Abstract: The novel phosphorylated derivatives of Lamivudine (5a-5l) as potential anti colon cancer agents are synthe- sized. These title compounds are designed based on the basic pyrimidine derivative lamivudine as a starting compound and reacted with various phosphorodichloridates followed by the introduction of bioactive groups at the phosphorus. Their structures were characterized by IR, 1 H, 13 C, 31 P NMR and mass spectral analyses. All the compounds were evaluated for their anti colon cancer activity against COLO-205 cell lines in vitro studies. Among them 5a and 5b emerged as lead compounds with 0.003 μM and 0.0001 μM values.
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TL;DR: These new structurally diversified set of α-aminophosphonates (4a-j) were evaluated for their anti-tumor activity on human chronic myeloid leukemia cells, human colon carcinoma cells along with non-cancerous human embryonic kidney cells.
63 citations
TL;DR: These compounds are potential candidates for further pharmacologic development to target ABAD to improve mitochondrial function and abolished Aβ-induced mitochondrial dysfunction as shown by increased cytochrome c oxidase activity and adenosine-5'-triphosphate levels, suggesting protective mitochondrial function effects of these synthesized compounds.
Abstract: Amyloid beta (Aβ) binding alcohol dehydrogenase (ABAD) is a cellular cofactor for promoting (Aβ)-mediated mitochondrial and neuronal dysfunction, and cognitive decline in transgenic Alzheimer’s disease (AD) mouse models. Targeting mitochondrial ABAD may represent a novel therapeutic strategy against AD. Here, we report the biological activity of small molecule ABAD inhibitors. Using in vitro surface plasmon resonance (SPR) studies, we synthesized compounds with strong binding affinities for ABAD. Further, these ABAD inhibitors (ABAD-4a and 4b) reduced ABAD enzyme activity and administration of phosphonate derivatives of ABAD inhibitors antagonized calcium-mediated mitochondrial swelling. Importantly, these compounds also abolished Aβ-induced mitochondrial dysfunction as shown by increased cytochrome c oxidase activity and adenosine-5'-triphosphate levels, suggesting protective mitochondrial function effects of these synthesized compounds. Thus, these compounds are potential candidates for further pharmacologic development to target ABAD to improve mitochondrial function.
48 citations
Cites background from "Design, Synthesis and Anti Colon Ca..."
...[46-50] Future plans include examination of the ability of these compounds to cross the blood brain barrier and further evaluation of the effects on mitochondrial and neuronal function, amyloid pathology, and behavior in an AD mouse model....
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TL;DR: The main objective of the present work is to carry out the QSAR studies for all the series of the compounds starting from 4a to 6j to find out their molecular descriptors and predict the biological properties, and to consider these molecules as potential antiviral drugs.
35 citations
Cites background from "Design, Synthesis and Anti Colon Ca..."
...The ester carbonyl stretching frequency was observed in the range of 1715–1745 cm 1 (Rao et al., 2011)....
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TL;DR: Activation of hPreP by small benzimidazole derivatives provide a promising avenue for AD treatment, and is suggested to be an attractive target for Alzheimer's drug design.
28 citations
Cites background from "Design, Synthesis and Anti Colon Ca..."
...We observed characteristic IR absorption readings in regions at: 3475– 3371 cm−1 and 3342–3330−1, for: N–H [37, 38], O–H [39, 40], respectively....
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TL;DR: Syntheses of a new series of biologically potent α‐aminophosphonates showed the best activity on two human cancer cell lines even though the majority of the compounds, and particularly 4l and 4p, have good cytotoxic activity against them.
Abstract: Syntheses of a new series of biologically potent α-aminophosphonates were accomplished by one-pot Kabachnik-Fields reaction using TiO2-SiO2 as solid supported catalyst under microwave irradiation conditions. The chemical structures of all the newly synthesized compounds were confirmed by analytical and spectral (IR, 1H, 13C, 31P NMR, and mass) data. Their anticancer nature was evaluated by screening the in vitro activity on two human cancer cell lines, HeLa and SK-BR-3. Compounds 4i and 4o showed the best activity on these cancer cells even though the majority of the compounds, and particularly 4l and 4p, have good cytotoxic activity against them.
21 citations
References
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TL;DR: A tetrazolium salt has been used to develop a quantitative colorimetric assay for mammalian cell survival and proliferation and is used to measure proliferative lymphokines, mitogen stimulations and complement-mediated lysis.
50,114 citations
"Design, Synthesis and Anti Colon Ca..." refers methods in this paper
...Cell proliferation was assayed by MTT (3-(4, 5dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide) assay as described by Mosmann (1983) [16]....
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Book•
01 Jan 1966
TL;DR: Common physical techniques used in purification chemical methods used in Purification purification of organic chemicals Purification of inorganic and metal organic chemicals general methods for the purification classification of classes of compounds and natural products biochemicals and related products as mentioned in this paper.
Abstract: Common physical techniques used in purification chemical methods used in purification purification of organic chemicals purification of inorganic and metal organic chemicals general methods for the purification of classes of compounds purification of natural products biochemicals and related products.
10,132 citations
"Design, Synthesis and Anti Colon Ca..." refers methods in this paper
...All solvents used for spectroscopic and other physical studies were reagent grade and were further purified by literature methods [15]....
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Brown University1, Harvard University2, International AIDS Society3, Stanford University4, University of British Columbia5, University of California, San Diego6, University of Alabama at Birmingham7, University of Colorado Denver8, Istituto Superiore di Sanità9, University of Paris10, University of California, San Francisco11
TL;DR: New data have provided a stronger rationale for earlier initiation of more aggressive therapy than previously recommended and reinforce the importance of careful selection of initial drug regimen for each patient for optimal long-term clinical benefit and adherence.
Abstract: Objective.—To provide recommendations for antiretroviral therapy based on information
available in mid-1998.Participants.—An international panel of physicians with expertise in antiretroviral
research and care of patients with human immunodeficiency virus (HIV) infection,
first convened by the International AIDS Society–USA in December 1995.Evidence.—The panel reviewed available clinical and basic science study
results (including phase 3 controlled trials; clinical, virologic, and immunologic
end point data; data presented at research conferences; and studies of HIV
pathophysiology); opinions of panel members were also considered. Recommendations
were limited to drugs available in mid-1998.Consensus Process.—Panel members monitor new clinical research reports and interim
results. The full panel meets regularly to discuss how the new information
may change treatment recommendations. Updated recommendations are developed
through consensus of the entire panel at each stage of development.Conclusions.—Accumulating data from clinical and pathogenesis studies continue
to support early institution of potent antiretroviral therapy in patients
with HIV infection. A variety of combination regimens show potency, expanding
choices for initial regimens for individual patients. Plasma HIV RNA assays
with increased sensitivity are important in monitoring therapeutic response;
however, more data are needed to determine precisely the HIV RNA levels that
define treatment failure. Long-term adverse drug effects are beginning to
emerge, requiring ongoing attention. Some issues regarding optimal long-term
approaches to antiretroviral management are unresolved. The increased complexity
in HIV management requires ongoing monitoring of new data for optimal treatment
of HIV infection.
1,151 citations
"Design, Synthesis and Anti Colon Ca..." refers background in this paper
...Lamivudine is a dideoxynucleoside analog reverse transcriptase inhibitor that is used in combination with other nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, and protease inhibitors in the treatment of HIV-1 infection as a component of currently recommended highly active antiretroviral therapy [4]....
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TL;DR: The combination of lamivudine and interferon appeared to increase the HBeAg seroconversion rate, particularly in patients with moderately elevated baseline aminotransferase levels, and the potential benefit of combining lamivUDine andInterferon should be investigated further in studies with different regimens of combination therapy.
Abstract: BACKGROUND, AIM, AND METHODS—Alpha interferon is the generally approved therapy for HBe antigen positive patients with chronic hepatitis B, but its efficacy is limited. Lamivudine is a new oral nucleoside analogue which potently inhibits hepatitis B virus (HBV) DNA replication. To investigate the possibility of an additive effect of interferon-lamivudine combination therapy compared with interferon or lamivudine monotherapy, we conducted a randomised controlled trial in 230 predominantly Caucasian patients with hepatitis B e antigen (HBeAg) and HBV DNA positive chronic hepatitis B. Previously untreated patients were randomised to receive: combination therapy of lamivudine 100 mg daily with alpha interferon 10 million units three times weekly for 16 weeks after pretreatment with lamivudine for eight weeks (n=75); alpha interferon 10 million units three times weekly for 16 weeks (n=69); or lamivudine 100 mg daily for 52 weeks (n=82). The primary efficacy end point was the HBeAg seroconversion rate at week 52 (loss of HBeAg, development of antibodies to HBeAg and undetectable HBV DNA).
RESULTS—The HBeAg seroconversion rate at week 52 was 29% for the combination therapy, 19% for interferon monotherapy, and 18% for lamivudine monotherapy (p=0.12 and p=0.10, respectively, for comparison of the combination therapy with interferon or lamivudine monotherapy). The HBeAg seroconversion rates at week 52 for the combination therapy and lamivudine monotherapy were significantly different in the per protocol analysis (36% (20/56) v 19% (13/70), respectively; p=0.02). The effect of combining lamivudine and interferon appeared to be most useful in patients with moderately elevated alanine aminotransferase levels at baseline. Adverse events with the combination therapy were similar to interferon monotherapy; patients receiving lamivudine monotherapy had significantly fewer adverse events.
CONCLUSIONS—HBeAg seroconversion rates at one year were similar for lamivudine monotherapy (52 weeks) and standard alpha interferon therapy (16 weeks). The combination of lamivudine and interferon appeared to increase the HBeAg seroconversion rate, particularly in patients with moderately elevated baseline aminotransferase levels. The potential benefit of combining lamivudine and interferon should be investigated further in studies with different regimens of combination therapy.
Keywords: chronic hepatitis B; hepatitis B virus; nucleoside analogue; lamivudine; alpha interferon; combination therapy; HBeAg seroconversion
496 citations
TL;DR: A novel nucleoside analog, 2'-deoxy-3'-thiacytidine (BCH-189), in which the 3' carbon of the ribose ring of 2'- deoxycytidine has been replaced by a sulfur atom, which had significant time- and dose-dependent antiviral activity against five different strains of human immunodeficiency virus type 1 (HIV-1).
Abstract: We describe a novel nucleoside analog, 2'-deoxy-3'-thiacytidine (BCH-189), in which the 3' carbon of the ribose ring of 2'-deoxycytidine has been replaced by a sulfur atom. In MT-4 T cells, this compound had significant time- and dose-dependent antiviral activity against five different strains of human immunodeficiency virus type 1 (HIV-1) (mean 50% inhibitory dose, 0.73 microM); known 3'-azido-3'-deoxythymidine (AZT)-resistant HIV-1 variants did not exhibit cross-resistance to it. BCH-189 also suppressed HIV-1 replication in the U937 monocytoid cell line as well as in primary cultures of human peripheral blood mononuclear cells; in these latter systems, suppression was fuller and longer lasting than that induced by AZT. Moreover, BCH-189 was less toxic than AZT in cell culture. BCH-189 may be a promising drug for the treatment of HIV-1-associated disease.
243 citations
"Design, Synthesis and Anti Colon Ca..." refers background in this paper
...a structurally novel potent anti-HIV analog BCH -189 (2'-3'-dideoxy-3'thiacytidine) [3], in which the methylene group at the 3 position of the ribose ring is replaced by a sulfur atom....
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