Jahangir Amin

Small molecule induced reactivation of mutant p53 in cancer cells

The p53 cancer mutant Y220C is an excellent paradigm for rescuing the function of conformationally unstable p53 mutants because it has a unique surface crevice that can be targeted by small-molecule stabilizers. Here, we have identified a compound, PK7088, which is active in vitro: PK7088 bound to the mutant with a dissociation constant of 140 μM and raised its melting temperature, and we have determined the binding mode of a close structural analogue by X-ray crystallography. We showed that PK7088 is biologically active in cancer cells carrying the Y220C mutant by a battery of tests. PK7088 increased the amount of folded mutant protein with wild-type conformation, as monitored by immunofluorescence, and restored its transcriptional functions. It induced p53-Y220C-dependent growth inhibition, cell-cycle arrest and apoptosis. Most notably, PK7088 increased the expression levels of p21 and the proapoptotic NOXA protein. PK7088 worked synergistically with Nutlin-3 on up-regulating p21 expression, whereas Nutlin-3 on its own had no effect, consistent with its mechanism of action. PK7088 also restored non-transcriptional apoptotic functions of p53 by triggering nuclear export of BAX to the mitochondria. We suggest a set of criteria for assigning activation of p53.

Synthesis and Biological Evaluation of JAHAs: Ferrocene-Based Histone Deacetylase Inhibitors.

N1-Hydroxy-N8-ferrocenyloctanediamide, JAHA (7), an organometallic analogue of SAHA containing a ferrocenyl group as a phenyl bioisostere, displays nanomolar inhibition of class I HDACs, excellent selectivity over class IIa HDACs, and anticancer action in intact cells (IC50 = 2.4 μM, MCF7 cell line). Molecular docking studies of 7 in HDAC8 (a,b) suggested that the ferrocenyl moiety in 7 can overlap with the aryl cap of SAHA and should display similar HDAC inhibition, which was borne out in an in vitro assay (IC50 values against HDAC8 (μM, SD in parentheses): SAHA, 1.41 (0.15); 7, 1.36 (0.16). Thereafter, a small library of related JAHA analogues has been synthesized, and preliminary SAR studies are presented. IC50 values as low as 90 pM toward HDAC6 (class IIb) have been determined, highlighting the excellent potential of JAHAs as bioinorganic probes.

Click JAHAs: conformationally restricted ferrocene-based histone deacetylase inhibitors

A small library of ferrocene-based 1,2,3-triazole-containing hydroxamic acids has been synthesised employing click chemistry: 7-(4-ferrocenyl-1H-1,2,3-triazol-1-yl)-N-hydroxyheptanamide, 4b, containing the 1,2,3-triazole moiety adjacent to the ferrocene group, displayed excellent HDAC inhibition and activity in cells, inhibiting the deacetylation of tubulin as well as inducing cell cycle arrest.

Diastereoselective synthesis of half-sandwich chiral-at-metal cobaltacycles by oxidative cyclisation

Reaction of chiral ester linked diynes with chlorotris(triphenylphosphine)cobalt(I) and sodium cyclopentadienide gave (η(5)-cyclopentadienyl)(triphenylphosphine) cobaltacyclopentadiene complexes as single chiral-at-metal diastereoisomers, including a non-racemic example synthesised in three steps from (S)-3-butyn-2-ol.