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Chemistry and Pharmacology of Naturally Occurring Flavoalkaloids
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Rashmi Gaur, Jyoti Gaur, Nikhilesh Kumar
The flavoalkaloids have a unique structure consisting of phenols and a basic nitrogen atom resulting from the convergence of specific biosynthetic pathways. Though these compounds are difficult to extract, they possess various biological properties, which cannot be obtained from flavonoids and alkaloids alone. One such example is flavopiridol (known as alvocidib), a semisynthetic flavoalkaloid that is used currently under clinical investigation as a potential CDK 9 kinase inhibitor for the treatment of various cancers (Senderowicz et al., 1999). Flavopiridol showed promising results in the treatment of chronic lymphocytic leukemia and acute myeloid leukemia, and will undergo stage III clinical trials in due time (Zeidner et al., 2015).
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Transcription factors are proteins that control the DNA transcriptional process by selectively binding to a target sequence in the promoter region of the relevant gene to stimulate or inhibit transcription. They work by modifying the activity of RNA Polymerase II (Pol II) to ensure that transcription occurs (or not) at the appropriate time and place in the genome. Cancer therapies based on inhibiting the transcription of oncogenes such as C-Myc, HIF-1, NFκB, and STAT-3 have been envisaged. A number of small molecules inhibitors have been reported such as alvocidib, echinomycin, PBD molecules (e.g., TSG-1301), and the hairpin polyamides that can bind to duplex DNA in a sequence-selective manner and inhibit transcription. Some of these molecules are described in Section 5.7.1.1.1, although none have reached the approval stage.
Overview of Molecular Pathways in Melanoma
Published in Sanjiv S. Agarwala, Vernon K. Sondak, Melanoma, 2008
While unable to therapeutically replace deleted tumor-suppressor proteins, there are other ways of mechanistically repairing and/or restoring cell cycle regulation. Varied drugs that function as CDK inhibitors are being investigated and include older agents, such as flavopiridol (alvocidib, Aventis Pharmaceuticals, Inc., Bridgewater, New Jersey, U.S.), as well as newer selective inhibitors that target one or several CDKs (103,104). The therapeutic goal of CDK inhibitors is to effect cell cycle arrest in lieu of aberrant regulatory controls, facilitating apoptotic tumor cell death (103). In metastatic melanoma, flavopiridol, a pan-CDK inhibitor, demonstrated stable disease in 7 of 16 patients treated but no objective responses (105). Novel small-molecule inhibitors, all under phase I investigation, include: PD-0332991 (Pfizer) which inhibits CDK 4/6 (106), SNS-032 (BMS-387032, Sunesis, South San Francisco, California, U.S.) which inhibits CDK 2/7/9, and ZK 304709 (Schering AG, Berlin, Germany) which inhibits CDK 1/2/4/7/9 as well as VEGFR 1/2/3 and PDGFR-β (107,108). Therapeutic agents aimed at epigenetic alterations as well as at the proteasome may be relevant in tumors with aberrant cell cycle controls.
An overview of novel therapies in advanced clinical testing for acute myeloid leukemia
Published in Expert Review of Hematology, 2023
Sangeetha Venugopal, Zhuoer Xie, Amer M. Zeidan
In the phase 1 trial of alvocidib, a potent, nonselective CDK-9 inhibitor in combination with ‘7 + 3’ chemotherapy in patients with newly diagnosed AML and non-favorable cytogenetics, was administered on days 1–3 prior to starting 7 + 3 [76]. There was no dose-limiting toxicity, and maximal tolerated dose of alvocidib was not reached. The most common grade ≥3 TEAE included diarrhea (44%) and tumor lysis syndrome (34%) which did not warrant treatment discontinuation. Alvocidib in combination with 7 + 3 demonstrated clinical activity with a CR rate of 65%. Of note, there was no correlation between MCL-1 dependence and treatment response in this cohort, although the analysis was limited by small numbers. However, further development of alvocidib was halted in May 2021 due to sponsor decision. Several other CDK 9 inhibitors such as AZD4573, CYC065 are in early phase clinical development.
Cyclin-dependent kinase (CDK) 9 and 4/6 inhibitors in acute myeloid leukemia (AML): a promising therapeutic approach
Published in Expert Opinion on Investigational Drugs, 2019
Daniel J. Lee, Joshua F. Zeidner
The integration of alvocidib into a timed sequential cytotoxic induction regimen for AML patients was originally conceived by Dr. Judith Karp and colleagues. Notably, an in vitro timed sequential therapy model of relapsed/refractory AML patient samples revealed a 4.3-fold increase in apoptosis and a significant increase in cytotoxicity with the addition of alvocidib followed by cytarabine versus either alvocidib or cytarabine alone [45]. These results revealed that alvocidib may potentiate the effects of cytotoxic chemotherapy in AML patients.
Analysis of plant-derived phytochemicals as anti-cancer agents targeting cyclin dependent kinase-2, human topoisomerase IIa and vascular endothelial growth factor receptor-2
Published in Journal of Receptors and Signal Transduction, 2021
Bishajit Sarkar, Md. Asad Ullah, Syed Sajidul Islam, MD. Hasanur Rahman, Yusha Araf
Cancer is defined as the uncontrolled proliferation and abnormal spread of the body’s specific cells. According to WHO, cancer was responsible for 13% of world deaths accounted in 2005. Moreover, projections have shown that cause-specific years of life lost (YLL) rate due to cancer has already increased in 2005 and 2015, and it will continue to be rising in the future. Millions of species of plants, animals, marine organisms and microorganisms act as attractive sources for new therapeutic candidate compounds. However, the development of novel agents from natural sources faces many obstacles that are not usually met when one deals with synthetic compounds. Moreover, there may be difficulties with identification, isolation, assessing, and obtaining the appropriate amounts of the active compounds in the sample [1,2]. The search for anti-cancer compounds from plant sources started in the 1950s with the discovery and development of the various natural compounds like vinca alkaloids, vinblastine, vincristine, and cytotoxic podophyllotoxins. In the recent years, new technologies have been developed by the scientists to enhance natural product drug discovery in an industrial manner. Indeed, several new anticancer agents of natural origin have been introduced to the market recently and there is a promising pipeline of natural products in cancer-related clinical trials [3–6]. Future advances in the directed biosynthesis of small molecules will improve the ability of the scientists to control the shape and topology of various small molecules and thus creating new anti-cancer compounds that will interact specifically with biological targets. In the future, plants (300,000–500,000 such species) will continue to be a vital and valuable resource for anticancer drug discovery. More than 60 compounds from different plant sources are currently in the pipeline as potential anticancer agents [7–10]. Many chemical and synthetic drugs are already available for treating cancers i.e. alvocidib, lenvatinib, and daunorubicin etc. These chemical drugs have many adverse effects like sepsis, diarrhea, stomach and bladder pain, hair loss, paralysis, joint pain etc. However, plant phytochemicals are considered as safe in this regard since they generally do not possess any adverse effect to the human health in appropriate doses [11–14]. Therefore, using alternatives from plants can have great potential for cancer treatment. Table 1 lists the potential phytochemicals used in the experiment.