New developments in natural products‐based anti‐AIDS research

Yu, Donglei; Morris‐Natschke, Susan L.; Lee, Kuo Hsiung̀

doi:10.1002/med.20075

Cited by 82 publications

(39 citation statements)

References 93 publications

(97 reference statements)

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“…Furthermore, a betulinic acid derivative, DSB [PA-457], is currently in phase II clinical trial as a first-in-class HIV maturation inhibitor34. We believe that the pharmacologic safety of betulinic acid and its ability to down regulate the expression of several genes involved in cell survival and chemoresistance provides a sufficient rationale for testing betulinic acid further in patients with MM.…”

Section: Discussionmentioning

confidence: 99%

Betulinic acid suppresses STAT3 activation pathway through induction of protein tyrosine phosphatase SHP‐1 in human multiple myeloma cells

Pandey

Sung

Aggarwal

2010

Intl Journal of Cancer

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STAT3 activation has been associated with survival, proliferation and invasion of various human cancers. Whether betulinic acid, a pentacyclic triterpene, can modulate the STAT3 pathway, was investigated in human multiple myeloma (MM) cells. We found that betulinic acid inhibited constitutive activation of STAT3, Src kinase, JAK1 and JAK2. Pervanadate reversed the betulinic acid-induced downregulation of STAT3 activation, suggesting the involvement of a protein tyrosine phosphatase (PTP). Furthermore, betulinic acid induced the expression of the PTP SHP-1 and silencing of the SHP-1 gene abolished the ability of betulinic acid to inhibit STAT3 activation and rescued betulinic acid-induced cell death. Betulinic acid also downregulated the expression of STAT3-regulated gene products such as bcl-xL, bcl-2, cyclin D1 and survivin. This correlated with an increase in apoptosis as indicated by an increase in the sub-G1 cell population and an increase in caspase-3-induced PARP cleavage. Consistent with these results, overexpression of constitutive active STAT3 significantly reduced the betulinic acid-induced apoptosis. Betulinic acid also enhanced the apoptosis induced by thalidomide (from 10 to 55%) and bortezomib (from 5 to 70%) in MM cells. Overall, our results suggest that betulinic acid downregulates STAT3 activation through upregulation of SHP-1, and this may have potential in sensitization of STAT3 overexpressing tumors to chemotherapeutic agents.

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Section: Discussionmentioning

confidence: 99%

Betulinic acid suppresses STAT3 activation pathway through induction of protein tyrosine phosphatase SHP‐1 in human multiple myeloma cells

Pandey

Sung

Aggarwal

2010

Intl Journal of Cancer

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“…The resulting virus particles are defective and noninfectious. In summary, 132 was found to be the first-in-class HIV maturation inhibitor, targeting the CA-SP1 region of gag 88,95. Compound 133 was easily formulated as in a salt form with good oral availability, was eliminated via glucuronidation, and was active in a SCID mouse model 96.…”

Section: Betulinic Acid Derivativesmentioning

confidence: 99%

Discovery and Development of Natural Product-Derived Chemotherapeutic Agents Based on a Medicinal Chemistry Approach

2010

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Medicinal plants have long been an excellent source of pharmaceutical agents. Accordingly, the long term objectives of the author's research program are to discover and design new chemotherapeutic agents based on plant-derived compound leads by using a medicinal chemistry approach, which is a combination of chemistry and biology. Different examples of promising bioactive natural products and their synthetic analogs, including sesquiterpene lactones, quassinoids, naphthoquinones, phenylquinolones, dithiophenediones, neo-tanshinlactone, tylophorine, suksdorfin, DCK, and DCP, will be presented with respect to their discovery and preclinical development as potential clinical trial candidates. Research approaches include bioactivity- or mechanism of action-directed isolation and characterization of active compounds, rational drug design-based modification and analog synthesis, as well as structure-activity relationship and mechanism of action studies. Current clinical trials agents discovered by the Natural Products Research Laboratories, University of North Carolina, include bevirimat (dimethyl succinyl betulinic acid), which is now in Phase IIb trials for treating AIDS. Bevirimat is also the first in a new class of HIV drug candidates called “maturation inhibitors”. In addition, an etoposide analog, GL-331, progressed to anticancer Phase II clinical trials, and the curcumin analog JC-9 is in Phase II clinical trials for treating acne and in development for trials against prostate cancer. The discovery and development of these clinical trials candidates will also be discussed.

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“…1-3 Among them, natural tetracyclic diterpenoids, especially ent- kaurane diterpenoids with exo- methylene cyclopentanone in the D-ring such as oridonin ( 1 ), ponicidin and phyllostachysin F (Figure 1), constitute an important class of natural products which exhibit considerable pharmacological activities including antitumor, antibacterial, anti-tuberculosis and anti-inflammatory effects. 4-7 …”

Section: Introductionmentioning

confidence: 99%

Novel Nitrogen-Enriched Oridonin Analogues with Thiazole-Fused A-Ring: Protecting Group-Free Synthesis, Enhanced Anticancer Profile, and Improved Aqueous Solubility

et al. 2013

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Oridonin (1), a complex ent-kaurane diterpenoid isolated from the traditional Chinese herb Isodon rubescens, has demonstrated great potential in the treatment of various human cancers due to its unique and safe anticancer pharmacological profile. Nevertheless, the clinical development of oridonin for cancer therapy has been hampered by its relatively moderate potency, limited aqueous solubility and poor bioavailability. Herein, we report the concise synthesis of a series of novel nitrogen-enriched oridonin derivatives with thiazole-fused A-ring through an efficient protecting group-free synthetic strategy. Most of them including compounds 7-11, 13 and 14 exhibited potent antiproliferative effects against breast, pancreatic and prostate cancer cells with low micromolar to submicromolar IC50 values, as well as markedly enhanced aqueous solubility. These new analogs obtained by rationally modifying the natural product have been demonstrated not only to significantly induce the apoptosis and suppress growth of triple-negative MDA-MB-231 breast cancer both in vitro and in vivo, but also effective against drug-resistant ER-positive MCF-7 clones.

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New developments in natural products‐based anti‐AIDS research

Cited by 82 publications

References 93 publications

Betulinic acid suppresses STAT3 activation pathway through induction of protein tyrosine phosphatase SHP‐1 in human multiple myeloma cells

Betulinic acid suppresses STAT3 activation pathway through induction of protein tyrosine phosphatase SHP‐1 in human multiple myeloma cells

Discovery and Development of Natural Product-Derived Chemotherapeutic Agents Based on a Medicinal Chemistry Approach

Novel Nitrogen-Enriched Oridonin Analogues with Thiazole-Fused A-Ring: Protecting Group-Free Synthesis, Enhanced Anticancer Profile, and Improved Aqueous Solubility

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