Structure-Activity Relationships of the Antimalarial Agent Artemisinin 10. Synthesis and Antimalarial Activity of Enantiomers of rac-5ß-Hydroxy-d-Secoartemisinin and Analogs: Implications Regarding the Mechanism of Action.

An efficient synthesis of rac-6-desmethyl-5ß-hydroxy-d-secoartemisinin 2, a tricyclic analog of R-(+)-artemisinin 1, was accomplished and the racemate was resolved into the (+)-2b and (-)-2a enantiomers via their Mosher Ester diastereomers. Antimalarial activity resided with only the artemisinin-like enantiomer R-(-)-2a. Several new compounds 9-16, 19a, 19b, 22 and 29 were synthesized from rac-2 but the C-5 secondary hydroxyl group was surprisingly unreactive. For example, the formation of carbamates and Mitsunobu reactions were unsuccessful. In order to assess the unusual reactivity of 2, a single crystal X-ray crystallographic analysis revealed a close intramolecular hydrogen bond from the C-5 alcohol to the oxepane ether oxygen (O-11). All products were tested in vitro against the W-2 and D-6 strains of Plasmodium falciparum. Several of the analogs had moderate activity in comparison to the natural product 1. Iron (II) bromide-promoted rearrangement of 2 gave, in 50% yield, the ring-contracted tetrahydrofuran 22, while the 5-ketone 15 provided a monocyclic methyl ketone 29 (50%). Neither 22 nor 29 possessed in vitro antimalarial activity. These results have implications in regard to the antimalarial mechanism of action of artemisinin.

Transforming the 2-week wait (2WW) pathway: management of breast pain in primary care.

Breast pain has no association with breast cancer yet is a frequent reason for referral from Primary to Secondary Care, often on an urgent (2-week wait) referral. The referral often causes significant patient anxiety, further heightened by screening mammograms and/or ultrasound scans in the absence of an associated red flag symptom or finding by the patient or general practitioner. This paper reports the pilot implementation of a specialist Primary Care Breast Pain Clinic in Mid-Nottinghamshire where patients were seen, examined without any imaging and assessed for their risk of familial breast cancer: numerous studies have reported 15%->30% of patients with breast pain only have a family history of breast cancer.177 patients with breast pain only were seen in this clinic between March, 2020 and April, 2021 with a 6-month interim suspension due to COVID-19. The mean age of patients was 48.4 years (range: 16-86). 172/177 (97.2%) patients required no imaging although there were three (1.7%) inappropriate referrals and two additional abnormalities (1.1%-hamartoma, thickening/tethering) that were referred onward. There were no cancers. 21 (12.4%) patients were identified to have an increased familial risk of breast cancer and were referred to the specialist familial cancer service. 170/177 patients completed an anonymous questionnaire on leaving the clinic. 167/169 (99%) were reassured regarding their breast pain, 155/156 (99%) were reassured of the Familial Risk Assessment, 162/168 (96%) were reassured regarding their personal risk assessment while 169/170 (99%) were 'extremely likely/likely to recommend the service'.This specialist Primary Care Breast Pain Clinic provides service improvement across all levels of care (Primary, Secondary and Tertiary). Patients were successfully managed in the community with high levels of patient satisfaction and together this obviated referral to secondary care. The familial breast cancer risk assessment also helped identify unmet need in the community.