Despite being the commonest severe inherited disorder affecting millions of people worldwide, treatment for SCD remains problematical. As complications of SCD follow from polymerisation of HbS and RBC sickling, there has been considerable effort directed at discovering novel anti-sickling reagents. Many of these have

been designed to interact directly with HbS, to stabilise the oxy conformation (increasing O2 affinity) and to inhibit polymerisation [9], [10] and [11]. Various carbonyl compounds were shown to reduce RBC sickling over forty years ago, with aromatic aldehydes more effective than aliphatic aldehydes [9]. The reactive aldehyde group is thought to form Schiff bases with Hb amino groups, particularly the AG-014699 in vitro terminal α1val, and thereby increase O2 affinity. Amongst the most potent of the aromatic aldehydes tested was o-vanillin [9] and [30]. Its isomer p-vanillin (vanillin) is also thought DZNeP manufacturer to react with αHis103 to promote the oxy conformation, with possible other interactions at key sites of polymer

contact (βHis116 and βHis117). In vivo, although vanillin itself is poorly absorbed, a pro-drug MX-1520 was shown to protect sickle rats against hypoxia [31]. A number of substituted benzaldehydes, notably 12C79 (also known as BW12C or valerosol) and 589C80 (BWA589C or tucaresol), were also designed to act in a similar manner but with greater binding ability to Hb [32], [33] and [34]. In experiments involving cyclical deoxygenation and re-oxygenation of sickle cells in vitro both were effective in maintaining intracellular K+, high MCV and better deformability [35]. Combination of these benzaldehydes to act via reducing HbS depolymerisation along with direct inhibition of the Gardos channel with clotrimazole and nitrendipine was synergistic in protecting sickle RBCs from shrinkage and K+ loss during episodes

of cyclical deoxygenation [36]. In clinical trials, 12C79 (valerosol) was effective in increasing O2 affinity of Hb both in normal HbAA individuals [37] and SCD patients [38] but had a rather short half life. Although 589C80 (tucaresol) with its longer half life and ability to improve haematological parameters in sickle patients, side-effects second included fever and cervical lymphadenopathy [39]. More recently, attention has turned to other potential anti-sickling reagents. Amongst these are the heterocyclic aldehydes (furanic compounds). They too have a similar action binding to α1val and also probably disrupting a key salt bridge with the C-terminal carboxyl group of arg141α [11]. One of them, 5HMF was found to be several times more potent than vanillin in inhibiting sickling [40]. It also protected sickle mice from hypoxia [11]. These findings are very encouraging and currently, 5HMF is the subject of clinical trials in SCD patients.