ABSTRACT
Type 2 diabetes mellitus (T2DM) is progressive in nature and leads to hyperglycemia-associated microvascular and macrovascular complications. Diabetic nephropathy (DN) is one of the most prominent microvascular complication induced by T2DM and is characterized by albuminuria and progressive loss of kidney function. Aggressive management of hyperglycemia and hypertension has been found effective in delaying the development and progression of DN. Although the conventional antidiabetic treatment is effective in the earlier management of hyperglycemia, the progressive loss of beta cells ultimately needs the addition of insulin to the therapy. The emergence of newer antidiabetic agents may address the limitations associated with conventional antidiabetic therapies, which not only improve the glycemic status but also effective in improving cardio-renal outcomes. Nevertheless, the exact role of these agents and their role in minimizing diabetes progression to DN still needs elaboration. The present review aimed to highlights the impact of these newer antidiabetic agents in the management of hyperglycemia and their role in delaying the progression of diabetes to DN/management of DN in patients with T2DM.
ABSTRACT
Griseofulvin (1) is an important antifungal agent that has recently received attention due to its antiproliferative activity in mammalian cancer cells. Comprehensive SAR studies have led to the identification of 2'-benzyloxy griseofulvin 2, a more potent analogue with low micromolar anticancer potency in vitro. Analogue 2 was also shown to retard tumor growth through inhibition of centrosomal clustering in murine xenograft models of colon cancer and multiple myeloma. However, similar to griseofulvin, compound 2 exhibited poor metabolic stability and aqueous solubility. In order to improve the poor pharmacokinetic properties, 11 griseofulvin analogues were synthesized and evaluated for biological activity and physiological stabilities including SGF, plasma, and metabolic stability. Finally, the most promising compounds were investigated in respect to thermodynamic solubility and formulation studies. The 2'-benzylamine analogue 10 proved to be the most promising compound with low µM in vitro anticancer potency, a 200-fold increase in PBS solubility over compound 2, and with improved metabolic stability. Furthermore, this analogue proved compatible with formulations suitable for both oral and intravenous administration. Finally, 2'-benzylamine analogue 10 was confirmed to induce G2/M cell cycle arrest in vitro.
