Significance Unlike conventional antiviral therapy, lethal mutagenesis is a therapeutic strategy that exploits the high mutation rates of certain viruses. It works by intentionally increasing the viral mutation rate, causing excessive error accumulation and viral population collapse. The mutagenic nucleoside analog 5-aza-5,6-dihydro-2′-deoxycytidine (KP1212) is specifically designed to use lethal mutagenesis against HIV. The mechanism of KP1212 mutagenesis was proposed to involve tautomerism—the repositioning of active protons on the nucleic acid base on a fast time scale. Using a multifaceted approach, we demonstrate that KP1212 exists in multiple tautomeric forms, and that the tautomeric distribution correlates with the mutagenic properties of KP1212. This work also provides a toolset for studying tautomerism in nucleic acids and developing the next-generation antiviral lethal mutagens.

Multinucleation is found in more than one third of tumors and is linked to increased tolerance for mutation, resistance to chemotherapy, and invasive potential. The integrity of the genome depends on proper execution of the cell cycle, which can be altered through mechanotransduction pathways as the tumor microenvironment stiffens during tumorigenesis. Here, we show that signaling downstream of matrix metalloproteinase-3 (MMP3) or TGFβ, known inducers of epithelial-mesenchymal transition (EMT), also promotes multinucleation in stiff microenvironments through Snail-dependent expression of the filament-forming protein septin-6, resulting in midbody persistence, abscission failure, and multinucleation. Consistently, we observed elevated expression of Snail and septin-6 as well as multinucleation in a human patient sample of metaplastic carcinoma of the breast, a rare classification characterized by deposition of collagen fibers and active EMT. In contrast, a soft microenvironment protected mammary epithelial cells from becoming multinucleated by preventing Snail-induced upregulation of septin-6. Our data suggest that tissue stiffening during tumorigenesis synergizes with oncogenic signaling to promote genomic abnormalities that drive cancer progression. These findings reveal tissue stiffening during tumorigenesis synergizes with oncogenic signaling to promote genomic abnormalities that drive cancer progression. .

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The purification of structurally similar compounds was investigated using selective impurity complex formation in solution followed by crystallization of the target compound. Two systems of structurally similar compounds, benzamide/benzoic acid (BAM/BA) and cinnamamide/cinnamic acid (CAM/CA), were chosen. Three reported co-formers that form co-crystals with both BA and CA were selected: isonicotinamide (INA), 2-amino-4,6-dimethylpyrimidine (DMP), and dimethylglyoxime (DMG). The addition of DMG to the BAM/BA system demonstrated the largest improvement of BAM purity. The amount of BA did not decrease with increasing amount of DMG added. For the CAM/CA system, adding DMP resulted in the largest CAM purity increase. Phase solubility diagrams were measured to calculate binding constants for 1:1 complexes. These binding constants were used as indications of the complexation level in the solution. For the CAM/CA system, the more complex formed in solution, the purer the CAM. This result was not seen in the BAM/BA system. The results indicate that, for difficult to purify compounds where the structurally similar impurities substitute in the crystal lattice, the use of additives which have the potential to complex with the impurity in solution can result in an increase in crystal purity. However, the correlation between the level of complexation and the purification result needs further verification.

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