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Complement-mediated diseases or complementopathies, such as Paroxysmal nocturnal hemoglobinuria (PNH), cold agglutinin disease (CAD), and transplant-associated thrombotic microangiopathy (TA-TMA), demand advanced complement diagnostics and therapeutics be adopted in a vast field of medical specialties, such as hematology, transplantation, rheumatology, and nephrology. The miracle of complement inhibitors as “orphan drugs” has dramatically improved morbidity and mortality in patients with otherwise life-threatening complementopathies. Efficacy has been significantly improved by upstream inhibition in patients with PNH. Different molecules may exert diverse characteristics in vitro and in vivo. Further studies remain to show safety and efficacy of upstream inhibition in other complementopathies. In addition, cost and availability issues are major drawbacks of current treatments. Therefore, further developments are warranted to address the unmet clinical needs in the field of complementopathies. This state-of-the-art narrative review aims to delineate novel insights into factor D inhibition as a promising target for complementopathies.

Brevetoxin A is the most potent neurotoxin secreted by Gymnodinium breve Davis, a marine organism often associated with harmful algal blooms known as ‘red tides’1,2,3. The compound, whose mechanism of action involves binding to and opening of sodium channels4,5,6,7, is sufficiently toxic to kill fish at concentrations of nanograms per ml (refs 3, 4) and, after accumulation in filter-feeding shellfish, to poison human consumers. The precise pathway by which nature constructs brevetoxin A is at present unknown8,9, but strategies for its total synthesis have been contemplated for some time. The synthetic challenge posed by brevetoxin A reflects the high complexity of its molecular structure: 10 oxygen atoms and a chain of 44 carbon atoms are woven into a polycyclic macromolecule that includes 10 rings (containing between 5 and 9 atoms) and 22 stereogenic centres. Particularly challenging are the 7-, 8- and 9-membered rings which allow the molecule to undergo slow conformational changes and force a 90° twist at one of its rings1,2,3,4,5,6. Here we describe the successful incorporation of methods that were specifically developed for the construction of these rings10,11 into an overall strategy for the total synthesis of brevetoxin A in its naturally occurring form. The convergent synthesis reported here renders this scarce neurotoxin synthetically available and, more importantly, allows the design and synthesis of analogues for further biochemical studies.

Alkenylethylzincs, obtained from the corresponding trialkenylboranes by transmetallation with diethylzinc, couple with aryl iodides in the presence of Pd(PPh 3 ) 4 , 0.19–0.28 mol%, to produce trisubstituted alkenes in good isolated yields. Both the transmetallation and subsequent coupling occur with complete retention of stereochemistry.