The discovery and development of small-molecule anticancer agents that are both highly efficacious and selectively targeted remains a formidable goal and challenge. Conventional chemotherapy regimens often employ the use of cytotoxic agents which fail to differentiate between normal and cancerous tissue and are thus limited by their high degree of toxicity to normal tissue. Antibody-drug conjugates (ADCs) represent an emerging class of biopharmaceutical therapeutics that deliver highly potent anticancer agents (payloads) selectively to tumors or components of the tumor microenvironment. ADCs are comprised of a drug (payload) which is joined through an appropriate linker to an antibody or engineered protein. Pairing both a high degree of selectivity through the antibody with a high degree of cytotoxicity through the payload, ADCs represent an emerging and promising class of chemotherapeutic agents. Two small-molecule payloads (KGP05 and KGP18, previously discovered in the Pinney Laboratory) function as both highly potent antiproliferative agents (cytotoxins) and as highly effective vascular disrupting agents (VDAs). Details regarding the synthesis of these payloads and the preparation of drug-linker constructs tethering these payloads to the protease cleavable dipeptide linker Val-Cit-PABOH, widely used in ADC research, are presented.