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Synthesis of Majusculamide D and Structural Analogs for Pancreatic Cancer

Eduardo Caro
Appointment Period: 2017-2018, Grant Year: [31]

Eduardo Caro

Majusculamide D (MJM-D) is a linear peptide initially discovered from a Lyngbya majuscula from the Marshall Islands and shown by Moore to be a potent cytotoxin; however, was not studied further. It is structurally related to the potently cytotoxic metabolite microcolin A; the latter inhibits HT-29 (colorectal adenocarcinoma) and IMR-32 (neuroblastoma) cells at subnanomolar IC50 values (0.3 nM). Initial SAR studies on the microcolins have demonstrated a striking loss of activity upon deoxygenation or protection of the C10 free hydroxy group or reduction of the pyrrolinone C2-C3 alkene (the 2,3- dihydromicrocolin A is 10,000 times less active than microcolin B in cell-based assays). On the other hand, the C22 OAc group can be replaced with an OH without any significant effect on the bioactivity.

We independently determined that MJM-D is a very potent compound as obtained from three Papua New Guinea extracts of Lyngbya sp., 1376G, 1408H and 1739H and a few mg were obtained for initial pharmacology studies. Our zone assay showed that it is highly PANC-1 selective with an IC50 of 96 ng/ml. Clonogenic studies yielded S10 values for 2h and 24h of >5 μg/ml, and the 168h exposure of 7 ng/ml, indicating that a chronic (daily x 5) treatment schedule would be the most effective. Insufficient material was available to complete the maximum tolerated dose which was >1.75 mg/kg. To meet supply needs as well as explore more thoroughly SAR in this molecular class, we have embarked on its total synthesis and have recently achieved its completion. We are currently optimizing some key steps, attempting a shorter and more concise synthesis of the octanoic amide side chain, and unequivocally proving the absolute configuration of this side chain via analytical methods. Based on previously reported SAR studies of microcolin A and B, we have determined several synthetic analogs that will give insight to the SAR of majusculamide. Additionally, we have mapped out a synthetic route that will provide hundred-milligram quantities of majusculamide D and related compounds to be able to evaluate its efficacy in vivo. This project has tremendous potential to lead towards the development of a novel class of anti-tumor compounds that specifically target pancreatic carcinoma.

PUBLICATIONS (resulting from this training)

Caro-Diaz, EJ, Valeriote F, Gerwick WH. (2018) Highly Convergent Total Synthesis and Assignment of Absolute configuration of Majusculamide D, a highly cell-selective cytotoxic metabolite for Moorea Sp. Org. Lett. In preparation.

Naman CB, Almaliti J, Armstrong L, Caro-Díaz EJ, Pierce ML, Glukhov E, Fenner A, Spadafora C, Debonsi HM, Dorrestein PC, Murray TF, Gerwick WH. (2017) Discovery and Synthesis of Caracolamide A, an Ion Channel Modulating Dichlorovinylidene Containing Phenethylamide from a Panamanian Marine Cyanobacterium cf. Symploca Species. J Nat Prod. 80(8):2328-2334. doi: 10.1021/acs.jnatprod.7b00367 PMID: 28783331