The design of C₂-symmetric biologically active molecules is a subject of interest to the scientific community. It provides the possibility of discovering medicine with higher biological potential than the parent drugs. Such molecules are generally produced by classic chemistry, considering the shortness of reaction sequence and the efficacy for each step. This review describes and analyzes recent advances in the field and emphasizes selected C₂-symmetric molecules (or axial symmetric molecules) made during the last 10 years. However, the description of the dimers is contextualized by prior work allowing its development, and they are categorized by their structure and/or by their properties. Hence, this review presents dimers composed of steroids, sugars, and nucleosides; known and synthetic anticancer agents; polyphenol compounds; terpenes, known and synthetic antibacterial agents; and natural products. A special focus on the anticancer potential of the dimers transpires throughout the review, notwithstanding their structure and/or primary biological properties.

Macrophage-mediated inflammation is known to be involved in the epithelial–mesenchymal transition (EMT) of various types of cancer. This makes macrophage-derived inflammatory factors prime targets for the development of new treatments. This study uncovers the therapeutic potential and action mechanism of DAB-2-28, a small-molecule derived from para-aminobenzoic acid, in the treatment of breast cancer. The luminal MCF-7 and the triple-negative MDA-MB-231 cancer cell lines used in this study represent, respectively, breast cancers in which the differentiation states are related to the epithelial phenotype of the mammary gland and breast cancers expressing a highly aggressive mesenchymal phenotype. In MCF-7 cells, soluble factors from macrophage-conditioned media (CM-MØ) induce a characteristic morphology of mesenchymal cells with an upregulated expression of Snail1, a mesenchymal marker, as opposed to a decrease in the expression of E-cadherin, an epithelial marker. DAB-2-28 does not affect the differential expression of Snail1 and E-cadherin in response to CM-MØ, but negatively impacts other hallmarks of EMT by decreasing invasion and migration capacities, in addition to MMP9 expression and gelatinase activity, in both MCF-7 and MDA-MB-231 cells. Moreover, DAB-2-28 inhibits the phosphorylation of key pro-EMT transcriptional factors, such as NFκB, STAT3, SMAD2, CREB, and/or AKT proteins, in breast cancer cells exposed to different EMT inducers. Overall, our study provides evidence suggesting that inhibition of EMT initiation or maintenance is a key mechanism by which DAB-2-28 can exert anti-tumoral effects in breast cancer cells.

The design of innovative compounds displaying anti-inflammatory activity in oncological context is a subject of great interest in drug development. It has been proved that a pro-inflammatory microenvironment which accelerates cancer growth and cellular differentiation is often present in malignant bladder tumor. In earlier work, we reported the synthesis of p-aminobenzoic acid derivatives that act as anti-inflammatory compounds able to inhibit the pro-inflammatory markers present in bladder cancer microenvironment. DAB-1 rapidly emerged as an effective lead candidate in this investigation, with its ability to shrink by 90% in 25 days the size of human bladder cancer tumors in an ectopic mouse model. This manuscript discloses the synthesis of 23 new hydrazide derivatives of DAB-1 and reports their in vitro and in vivo biological evaluation. It was discovered that most of the new compounds are essentially nontoxic against RAW 264.7 cells, as evaluated by an MTT assay. Anti-inflammatory activity of the new derivatives was investigated by evaluation of their impact on cellular nitric oxide production, measured by a Griess assay. Some compounds did significatively inhibit nitric oxide production much more effectively than the original DAB-1. Striking activity of 14, which is around four times more potent than DAB-1, promotes this derivative as new lead compound in this study. The study of these analogs reveals that a phenolic/anisole core is a key component to achieve high biological activity. Furthermore, mice models of acute inflammation and invasive BCa tumors were used to assess the in vivo impact of derivative 14, and it was found that this compound does reduce inflammation in these mice, possess similar anti-inflammatory activity but higher anti-tumoral activity compared to DAB-1 with no apparent signs of toxicity.

The total synthesis of cyclotripeptidic natural products possessing a central piperazino[2,1-b]quinazolin-3,6-dione core is described, through an original strategy involving the pivotal cyclocondensation of an electrophilic homoserine lactone intermediate. The alkylidene group was spontaneously installed by autooxidation during the cyclocondensa-tion process, while the propionamide side-chain was introduced through the nickel-catalyzed aminocarbonylation of a bromoethyl intermediate. This last reaction is unprecedented on such highly functionalized intermediates. Finally, we explored structural modifications and interconversions of the natural products. Overall, this work led to anacine, au-rantiomide C, polonimide A and C, and verrucine F.