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Simple Summary: Cancer chemotherapy is dominated by cytotoxic drugs that non-selectively kill proliferating cells by blocking DNA replication and inducing apoptosis. Some natural anticancer products are less toxic to normal, slow-replicating cells but kill aggressive tumor cells. The combination of two structural isomers of pentacyclic triterpenes, oleanolic acid and ursolic acid, showed potent cytotoxic activity in human breast cancer cells in vitro by inducing cytotoxic autophagy at a significantly lower dose than previously reported. They were nontoxic to breast epithelial cells. Their activity was mainly due to the inhibition of AKT-mediated cell survival and the inhibition of the mammalian target of rapamycin (mTOR) signaling pathway, a central regulator of cell metabolism, growth, and proliferation. The compounds were equally effective against ER+ and triple-negative breast cancer cells. Combining low doses of nontoxic inhibitors of PI3k kinase increased the activities of these compounds. In contrast, inhibition of autophagy by 3-methyl adenine annulled their activity, demonstrating that cytotoxic autophagy may be the dominant mechanism of cell death. These compounds have potential for cancer therapy in neoadjuvant or adjuvant settings. Background: Oleanolic acid (OA) and Ursolic acid (UA) are bioactive triterpenoids. Reported activities vary with the dose used for testing their activities in vitro. Studies using doses of ≥20 µM showed apoptosis activities in cancer cells. However, reported drug levels in circulation achieved by oral administration of UA and OA are ≤2 µM, thus limiting their use for treatment or delivering a combination treatment. Materials and Methods: The present report demonstrates the efficacy of OA, UA, and OA + UA on tumor cell-specific cytotoxicity at low doses (5 µM to 10 µM) in breast cancer (BrCa) cell lines MCF7 and MDA-MB231. Results: The data show that both OA and UA killed BrCa cells at low doses, but were significantly less toxic to MCF-12A, a non-tumorigenic cell line. Moreover, OA + UA at ≤10 µM was lethal to BrCa cells. Mechanistic studies unraveled the significant absence of apoptosis, but their cytotoxicity was due to the induction of excessive autophagy at a OA + UA dose of 5 µM each. A link to drug-induced cytotoxic autophagy was established by demonstrating a lack of their cytotoxicity by silencing the autophagy-targeting genes (ATGs), which prevented OA-, UA-, or OA + UA-induced cell death. Further, UA or OA + UA treatment of BrCa cells caused an inhibition of PI3 kinase-mediated phosphorylation of Akt/mTOR, the key pathways that regulate cancer cell survival, metabolism, and proliferation. Discussion: Combinations of a PI3K inhibitor (LY294002) with OA, UA, or OA + UA synergistically inhibited BrCa cell survival. Therefore, the dominance of cytotoxic autophagy by inhibiting PI3K-mediated autophagy may be the primary mechanism of PTT-induced anticancer activity in BrCa cells. Conclusion: These results suggest it would be worthwhile testing combined OA and UA in clinical settings. [ABSTRACT FROM AUTHOR]

Simple Summary: Advanced urinary bladder cancer (BCa) is characterized by rapid progression and development of therapy resistance. Despite all the available therapies, the five-year survival of metastatic BCa is a dismal 8% or lower. Many conjugates and additives of the natural polyphenol curcumin were developed and tested for potential therapeutic for cancers, with little success in vivo due to their rapid elimination and poor tissue penetrance. We tested a novel molecular hybrid CMC-2 composed of a curcumin scaffold conjugated to two dichloroacetate and glycine molecules. CMC-2 showed significantly higher antiproliferative and anti-survival activities against BCa than its parent compounds. Further, it was equally effective against chemotherapy-naïve and multidrug-resistant BCas (MDR-BCa). When tested in vivo using BCa xenograft in athymic mice, CMC-2 significantly delayed tumor growth without systemic toxicity. The mechanism of anticancer activity of CMC-2 was the induction of excessive oxidative stress in the cancer cells, leading to apoptotic cell death. These results show the potential of CMC-2 as a nontoxic oral treatment for high-grade bladder cancers. Tumor cells produce excessive reactive oxygen species (ROS) but cannot detoxify ROS if they are due to an external agent. An agent that produces toxic levels of ROS, specifically in tumor cells, could be an effective anticancer drug. CMC-2 is a molecular hybrid of the bioactive polyphenol curcumin conjugated to dichloroacetate (DCA) via a glycine bridge. The CMC-2 was tested for its cytotoxic antitumor activities and killed both naïve and multidrug-resistant (MDR) bladder cancer (BCa) cells with equal potency (<1.0 µM); CMC-2 was about 10–15 folds more potent than curcumin or DCA. Growth of human BCa xenograft in mice was reduced by >50% by oral gavage of 50 mg/kg of CMC-2 without recognizable systemic toxicity. Doses that used curcumin or DCA showed minimum antitumor effects. In vitro, the toxicity of CMC-2 in both naïve and MDR cells depended on increased intracellular ROS in tumor cells but not in normal cells at comparable doses. Increased ROS caused the permeabilization of mitochondria and induced apoptosis. Further, adding N-Acetyl cysteine (NAC), a hydroxyl radical scavenger, abolished excessive ROS production and CMC-2's cytotoxicity. The lack of systemic toxicity, equal potency against chemotherapy -naïve and resistant tumors, and oral bioavailability establish the potential of CMC-2 as a potent drug against bladder cancers. [ABSTRACT FROM AUTHOR]

Pyridyloxy-directed Ir(III)-catalyzed diacylmethylation of protected tyrosines was achieved with alkyl and (hetero)aryl sulfoxonium ylides, furnishing tyrosine-based unnatural amino acids in good yields. Furthermore, the late stage exemplification of the strategy was successfully accomplished in tyrosine-containing dipeptides, tripeptides and tetrapeptides in moderate yields. This methodology is distinguished by its site-selectivity, tolerance of sensitive functional groups, scalability, and retention of the chiral configuration for tyrosine motifs. [ABSTRACT FROM AUTHOR]

Cancer remains a formidable global health challenge, with current treatment modalities such as chemotherapy, radiotherapy, surgery, and targeted therapy often hindered by low efficacy and adverse side effects. The indole scaffold, a prominent heterocyclic structure, has emerged as a promising candidate in the fight against cancer. This review consolidates recent advancements in developing natural and synthetic indolyl analogs, highlighting their antiproliferative activities against various cancer types over the past five years. These analogs are categorized based on their efficacy against common cancer types, supported by biochemical assays demonstrating their antiproliferative properties. In this review, emphasis is placed on elucidating the mechanisms of action of these compounds. Given the limitations of conventional cancer therapies, developing targeted therapeutics with enhanced selectivity and reduced side effects remains a critical focus in oncological research. [ABSTRACT FROM AUTHOR]

Pivaloyl‐directed Rh(III)‐catalyzed regioselective C7Ar‐H functionalization of protected tryptophans were accomplished with 1,4‐benzoquinones, furnishing a series of quinone‐appended tryptophan‐based unnatural amino acids in high yields. Further, the late stage functionalization on tryptophan‐containing dipeptides was achieved with 1,4‐benzoquinones in moderate reactivity. [ABSTRACT FROM AUTHOR]