ABSTRACT
We report our progress towards the synthesis of Urukthapelstatin A (Ustat A) and two analogues. Our retrosynthetic strategy involved the synthesis of three fragments: a tri-heteroaromatic moiety, a phenyl oxazole fragment, and a dipeptide. Described are the syntheses of three unique tri-heteroaromatic moieties. In addition, the corresponding linear precursors of Ustat A and two analogues are presented.
ABSTRACT
Utilizing the structure-activity relationship we have developed during the synthesis of the first two generations and mechanism of action studies that point to the interaction of these molecules with the key oncogenic protein Hsp90, we report here the design of 32 new Sansalvamide A derivatives and their synthesis. Our new structures, designed from previously reported potent compounds, were tested for cytotoxicity on the HCT116 colon cancer cell line, and their binding to the biological target was analyzed using computational studies involving blind docking of derivatives using Autodock. Further, we show new evidence that our molecules bind directly to Hsp90 and modulate Hsp90's binding with client proteins. Finally, we demonstrate that we have integrated good ADME properties into a new derivative.
Subject(s)
Antineoplastic Agents/chemical synthesis , Depsipeptides/chemistry , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Amino Acid Sequence , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Binding Sites , Cell Line, Tumor , Computer Simulation , Depsipeptides/chemical synthesis , Depsipeptides/toxicity , Drug Design , HSP90 Heat-Shock Proteins/metabolism , Humans , Protein Structure, Tertiary , Structure-Activity RelationshipABSTRACT
Described is the SAR of 18 di-sansalvamide A derivatives and the mechanism of action of the most potent compound. We show that this scaffold is a promising lead in the development of novel cancer therapeutics because it is cytotoxic at nanomolar potency, inhibits a well-established oncogenic target (Hsp90), and does not share structural motifs with current drugs on the market.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Depsipeptides/chemistry , Depsipeptides/pharmacology , Antineoplastic Agents/chemical synthesis , Depsipeptides/chemical synthesis , Drug Delivery Systems , HSP90 Heat-Shock Proteins/antagonists & inhibitors , HeLa Cells , Humans , Structure-Activity RelationshipABSTRACT
We report an extensive structure-activity relationship (SAR) of 78 compounds active against two pancreatic cancer cell lines. Our comprehensive evaluation of these compounds utilizes SAR that allow us to evaluate which features of potent compounds play a key role in their cytotoxicity. This is the first report of 19 new second-generation structures, where these new compounds were designed from the first generation of 59 compounds. These 78 structures were tested for their cytotoxicity and this is the first report of their activity against two pancreatic cancer cell lines. Our results show that out of 78 compounds, three compounds are worth pursuing as leads, as they show potency of 55% in both cancer cell lines. These three compounds all have a common structural motif, two consecutive d-amino acids and an N-methyl moiety. Further, of these three compounds, two are second-generation structures, indicating that we can incorporate and utilize data from the first generation to design potency into the second generation. Finally, one analog is in the mid nanomolar range, and has the lowest IC(50) of any reported San A derivative. These analogs share no structural homology to current pancreatic cancer drugs, and are cytotoxic at levels on par with existing drugs treating other cancers. Thus, we have established Sansalvamide A as an excellent lead for killing multiple pancreatic cancer cell lines.
Subject(s)
Antineoplastic Agents/chemistry , Depsipeptides/chemistry , Pancreatic Neoplasms/drug therapy , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , Cell Line, Tumor , Depsipeptides/chemical synthesis , Depsipeptides/toxicity , Drug Design , Drug Resistance, Neoplasm/drug effects , Drug Screening Assays, Antitumor , Humans , Structure-Activity RelationshipABSTRACT
A key feature for any chemotherapeutic agent is a favorable conformation when it is presenting itself to its intended target. Numerous macrocycles have been identified as having antitumor activity and have been a source of lead compounds in anticancer research. The macrocyclic scaffold restricts bond rotation, therefore macrocycles maintain a relatively rigid conformation compared to their linear counterparts. This review discusses recent progress in the development of macrocyclic versions of linear compounds with known antitumor activity, and describes how restrictions in molecular conformation affect tumor inhibition.
