Several natural product inspired fused and spiro-heterocyclic scaffolds were prepared by ring distortion and ring construction strategies and evaluated for anti-breast cancer activity. A facile domino Pictet-Spengler lactamization (PSL) afforded nine natural product inspired indolo[2,3-a]quinolizidine and indolo[8,7-b]indolizidine scaffolds which are converted to seven other scaffolds by functional group transformation, ring distortion and ring construction strategies. In vitro screenings of this library of sixteen scaffolds with six distinct architectures against MCF7 cell lines afforded two compounds (10 and 21) with modest activity. Principal component analysis of this library against databases of FDA approved drugs, commercial compounds and FDA approved breast cancer compounds indicated an eclectic mix of structures among the molecules. © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.