Toyocamycin is a nucleoside- type antibiotic analogue of adenosine, isolated from Streptomyces species. Toyocamycin is an antibiotic first isolated by Nishimura et al. from a new species of Streptomyces (St. toyocaensis), with a rather specific antibiotic spectrum. It strongly inhibits Candida albicans and Mycobacterium tuberculosis, without notable action on other microorganisms, such as many gram-positive and gramnegative bacteria, fungi, and yeast. Toyocamycin is an anti-tumor antibiotic with various target activities. Toyocamycin is a potent inhibitor of RNA self-cleavage in mammalian cells. It also inhibits phosphatidylinositol kinase, a cell proliferation regulator. Toyocamycin can suppress thapsigargin-, tunicamycin- and 2-deoxyglucose-induced XBP1 mRNA splicing in HeLa cells. This suppression doesn’t affect the activating of transcription factor 6 (ATF6) and PKR-like ER kinase (PERK)’s activation. Toyocamycin prevents IRE1a-induced XBP1 mRNA cleavage in vitro. In mammalian cells, toyocamycin inhibits RNA synthesis. Toyocamycin induces apoptosis of MM cells including bortezomib-resistant cells at nanomolar levels in a dose-dependent manner. It also inhibited growth of xenografts in an in vivo model of human multiple myeloma. It is also a lead compound for developing anti-MM therapy and XBP1 as an appropriate molecular target for anti-multiple myeloma therapy. Toyocamycin was the first identified small-molecule inhibitor of Rio1, showing mixed inhibition. This mode of action of toyocamycin results from its dual activity towards the Rio1 kinase. On the one hand, toyocamycin acts as an ATP-competitive inhibitor, and on the other hand, it stabilizes the less catalytically active oligomeric isoform of the Rio1 kinase.

Parthenolide is a sesquiterpene lactone found in Tanacetum that exhibits anticancer chemotherapeutic, anti-metastatic, anti-angiogenic, anti-inflammatory, and antinociceptive activities. Parthenolide acts as a partial agonist at transient receptor potential ankyrin 1 (TRPA1) channels and desensitizes them, preventing release of calcitonin gene-related peptide (CGRP). Additionally, parthenolide inhibits ATPase activity of NLRP3 and protease activity of caspase 1. In multiple myeloma cells, parthenolide decreases expression of NF-κB, VEGF, and IL-6 and increases expression of IκB kinase, inhibiting cell migration and tubule formation. In non-small cell lung cancer (NSCLC) cells, parthenolide decreases levels of MCL-1 and increases levels of MAIP-1, triggering ER stress and inducing cell cycle arrest and apoptosis. In breast cancer cells, this compound activates NADPH oxidase and increases ROS generation, increasing levels of p-JNK and downregulating NF-κB, VEGF, and matrix metalloproteinases 2 and 9 (MMP2/9); in vivo, parthenolide inhibits tumor growth and metastasis. Parthenolide has being shown to have agonistic activity against adiponectin receptor 2. Parthenolide is in phase I clinical trials by Ashbury Biologicals for the treatment of cancer. However, there is no recent report of this research.

δ-Tocopherol (δ-T) is a chiral organic molecule belonging to the group of tocopherol, that vary in their degree of methylation of the phenol moiety of the chromanol ring. It was revealed, that δ-Tocopherol had a more potent anticancer activity in solid tumors compared to the other tocopherols, δ-T possessed antileukemic activity of in acute myeloid leukemia (AML). δ-T induced tumor cell death through peroxisome proliferator-activated receptor γ (PPAR-γ) induction, cyclin-D1 inhibition, and modulation of redox balance. In addition, on animal models was found, that δ-tocopherol was more active than α- or γ-tocopherol in inhibiting lung tumor growth, possibly through trapping reactive oxygen and nitrogen species and inducing apoptosis.

Diosmetin is the aglycone of the flavonoid glycoside diosmin, which occurs naturally in citrus fruits. Diosmetin is found in the legume Acacia farnesiana Wild and Olea europaea L. leaves. Diosmin is hydrolyzed to its aglycone diosmetin by intestinal microflora enzymes before its absorption into the body. Pharmacologically, diosmetin is reported to exhibit anticancer, antimicrobial, antioxidant, oestrogenic and anti-inflammatory activities. Diosmetin increased inhibitory GSK-3beta phosphorylation, while selectively reducing gamma-secretase activity, Abetta generation, tau hyperphosphorylation and pro-inflammatory activation of microglia in vitro, without altering Notch processing. Therefore, diosmetin could be considered as potential candidate for novel anti- Alzheimer's disease therapy. Diosmetin is ER-beta agonist and potential novel drug for the acute myeloid leukemia treatment.

Roquinimex (Linomide, LS 2616) is a quinoline-3-carboxamide with pleiotropic immune modulating capacity and it has therapeutic effects in several experimental animal models of autoimmune diseases. Linomide has been evaluated in clinical trials for multiple sclerosis, and was indeed shown to have disease inhibitory effects. However, due to unexpected side effects recorded in patients treated with Linomide, premature termination of clinical trials was required. The basic mechanism(s) of action of Linomide in inducing beneficial effects in autoimmune diseases is still elusive. Some experimental evidence indicates that Linomide influences the regulation of the cytokine profile, resulting in the inhibition of autoimmune and inflammation pathologies. Roquinimex possesses potential antineoplastic activity. Roquinimex inhibits endothelial cell proliferation, migration, and basement membrane invasion; reduces the secretion of the angiogenic factor tumor necrosis factor alpha by tumor-associated macrophages (TAMs); and inhibits angiogenesis. Roquinimex was in phase III clinical trials with Pharmacia Corporation in Europe and the US for the treatment of multiple sclerosis.

Enocitabine is an anti-cancer nucleoside that was developed for the treatment of acute myeloid leukemia. Although the exact mechanism of its action is unknow, Enocitabine effectively inhibits tumor cell growht in vitro and the inhibition is supposed to be related to its metabolism to Ara-C, an inhibitor of DNA polymerase. The drug was approved in Japan and Korea and was marketed under the name Sunrabin, however, its current marketing status is unknown and is assumed to be discontinued.

Vosaroxin is a small molecule and a naphthyridine analogue with antineoplastic activity. This quinolone-based topoisomerase II inhibitor is a new therapeutic for acute myeloid leukemia (AML). Being a DNA intercalating topoisomerase II inhibitor that causes the induction of apoptosis via double-strand DNA breaks vosoroxin is chemically distinct from other topoisomerase inhibitors with its stable quinolone-based core. Due to the stability of this core, vosaroxin is not associated with significant formation of toxic metabolites, free radicals, or reactive oxygen species, which are associated with off-target organ damage and cardiotoxicity. Furthermore, vosaroxin evades two common mechanisms of drug resistance, as it is not a substrate for the P-glycoprotein efflux pump and its activity is maintained in cells with p53 deletion. Vosaroxin has beeт tested in several investigator-sponsored studies, both as a single-agent and in combination with other therapies, for the treatment of AML and myelodysplastic syndromes. Both the U.S. Food and Drug Administration (FDA) and European Commission have granted orphan drug designation to vosaroxin for the treatment of AML. Additionally, vosaroxin has been granted fast track designation by the FDA for the potential treatment of relapsed or refractory AML in combination with cytarabine. Vosaroxin is an investigational drug that has not been approved for use in any jurisdiction. The trademark name QINPREZO is conditionally accepted by the FDA and the EMA as the proprietary name for the vosaroxin drug product candidate.

Vorasidenib (also known as AG 881) was developed as an isocitrate dehydrogenase (IDH) type 1 in the cytoplasm and type 2 in the mitochondria, with potential antineoplastic activity. It is known that IDH is an essential enzyme for cellular respiration in the tricarboxylic acid (TCA) cycle. Isocitrate dehydrogenases 1 and 2 (IDH1/2) are homodimeric enzymes that catalyze the conversion of isocitrate to α-ketoglutarate (α-KG) in the tricarboxylic acid cycle. Vorasidenib participated in phase I clinical trials in patients with advanced hematologic malignancies and in gliomas.

Vorasidenib (also known as AG 881) was developed as an isocitrate dehydrogenase (IDH) type 1 in the cytoplasm and type 2 in the mitochondria, with potential antineoplastic activity. It is known that IDH is an essential enzyme for cellular respiration in the tricarboxylic acid (TCA) cycle. Isocitrate dehydrogenases 1 and 2 (IDH1/2) are homodimeric enzymes that catalyze the conversion of isocitrate to α-ketoglutarate (α-KG) in the tricarboxylic acid cycle. Vorasidenib participated in phase I clinical trials in patients with advanced hematologic malignancies and in gliomas.

Vorasidenib (also known as AG 881) was developed as an isocitrate dehydrogenase (IDH) type 1 in the cytoplasm and type 2 in the mitochondria, with potential antineoplastic activity. It is known that IDH is an essential enzyme for cellular respiration in the tricarboxylic acid (TCA) cycle. Isocitrate dehydrogenases 1 and 2 (IDH1/2) are homodimeric enzymes that catalyze the conversion of isocitrate to α-ketoglutarate (α-KG) in the tricarboxylic acid cycle. Vorasidenib participated in phase I clinical trials in patients with advanced hematologic malignancies and in gliomas.