Curcumin is known for its therapeutic properties; among these, antioxidant, anti-inflammatory and anti-cancer ones stand out. Besides, curcumin metal complexes have shown widespread application in medicine and can be exploited as lead structures for developing metal-based drugs. Unfortunately, curcumin is poorly bioavailable, mainly due to its instability in physiological conditions; this weakness is tightly connected to the presence of the β-diketo moiety undergoing tautomeric equilibrium. Stability and metal-chelating ability can be tuned by modulating the electronic effects and steric hindrance close to the β-diketo moiety; in addition, formation of a metal complex shifts the tautomeric equilibrium towards the β-keto–enol form and increases stability in biological media. Among the metals used in clinical therapy, gallium nitrate has shown to have significant antitumor activity against non-Hodgkin lymphoma and bladder cancer, thus indicating that gallium-based drugs have potential for further development as antineoplastic agents with improved therapeutic activity. Curcuminoids have demonstrated high affinity for gallium(III), allowing the formation of stable positively charged M:L 1:2 β-diketonate complexes that benefit from the therapeutic activity of both the metal and the ligand. Seven new curcumin derivatives were synthesized and completely characterized. The new derivatives retain the solvent-dependent keto–enol tautomerism, with the prevalence of the diketo form in aqueous solution. Enhanced stability in simulated physiological conditions was observed in comparison to the lead compound curcumin. The presence of Ga³⁺ anticipates the dissociation of the enolic proton, allowing chelate complex formation, and simultaneously it shifts the tautomeric equilibrium towards the keto–enol form. A complete ¹H/¹³C NMR and UV–Vis study was performed to define the metal-to-ligand stoichiometry ratio and the overall stability constants. In addition, we demonstrated that some of the derivatives have increased antiproliferative activity on colon cancer cells compared to curcumin and antioxidant properties. On the whole, the synthesized curcumin-based molecules may act as new gallium(III) chelators with improved stability with respect to curcumin and could open interesting perspectives for the development of novel therapeutic agents for cancer.

Background/Objectives: Rarely, primary (PriCs) or metastatic (metECs) carcinomas occur in the episiotomy site. Methods: A systematic literature review of metECs was carried out. We reviewed the PRISMA guidelines and the Scopus, Pubmed, and Web of Science databases. Results: We found 21 carcinomas; all of them were cervical carcinomas (11 squamous, SCC; 6 adenocarcinomas; 3 adenosquamous; 1 SCC or adenocarcinoma) diagnosed during pregnancy (38%) or 0.25–8 months postpartum (57%). SCCs were larger (mean size: 4.8 cm). At presentation, only two cases were pN+, and no distant metastases were found, excluding four episiotomy metastases (one anticipating the cervical cancer diagnosis); the remaining episiotomy metastases (mean size: 3 cm; one multifocal) were found at follow-up (these were first metastases in 86% of cases). The time range from the episiotomy/last delivery to first episiotomy metastasis was 1–66 (mean, 12.3) months. Treatment was variable: hysterectomy (71%) ± lymphadenectomy (67%) and/or adjuvant treatment (19%); chemoradiation/radiotherapy alone (24%). A total of 90% of cases recurred after 18 days to 66 months (mean, 12 months). At last follow-up, ten patients (48%) were disease-free after 12–120 (mean, 63.5) months, two patients (10%) were alive with disease, and nine (42%) patients died of disease after 6–36 (mean, 12.5) months (including two never-cleared/progressing cases). Conclusions: PriCs and metECs are rare. Iatrogenic/obstetric implantation or vascular dissemination of cervical cancer at the site of episiotomy may occur. For episiotomy lesions, accurate gynecological/perineal examination is required, and biopsy can be considered. Larger studies are required in order to determine treatment guidelines. Compared to PriCs, metECs occurred in younger (premenopausal) patients, were not associated with endometriosis, and demonstrated slightly smaller size and shorter mean time from episiotomy to episiotomy metastases, with a higher likelihood of a less favorable prognosis.