Several cardiac glycosides, including digoxin, digitoxin, and proscillaridin A, have been originally identified as cardiomyocyte modulators and are currently being investigated for their anticancer properties. These cardiac glycosides are generally classified into cardenolides and bufadienolides, which bear butenolide and pyrone D-ring functionality, respectively, and have exhibited remarkable in vitro toxicity in various cancerous cell lines. As simple modifications on steroidal small molecules have demonstrated success in augmenting bioavailability or enhancing downstream biological activities, we sought to prepare synthetic analogs of proscillaridin A, a bufadienolide isolated from the genus Scilla. We synthesized two novel analogs of proscillaridin A bearing acetate esters or a dimethyl ketal to investigate how strategies of ketalization or acetylation of the A-ring allylic glycoside might alter its anticancer properties. The antiproliferative activity of these compounds was evaluated alongside proscillaridin A and two model cardiac glycosides, digoxin and digitoxin, across several colorectal and liver cancer cell lines. Through a diverse panel of cell viability and cytotoxicity experiments, reporter assays, and cell cycle and protein marker analysis by flow cytometry, we find that ketalization of the glycan of proscillaridin A provides similar, and in some cases enhanced, in vitro potency. This study establishes the foundation for current and further in vitro and in vivo evaluation of glycan analogs of proscillaridin A.